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  • 1.
    Aguilar, Helena
    et al.
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Urruticoechea, Ander
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Halonen, Pasi
    The Netherlands Cancer Institute, Amsterdam.
    Kiyotani, Kazuma
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Mushiroda, Taisei
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Barril, Xavier
    University of Barcelona, Catalonia, Spain.
    Serra-Musach, Jordi
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Islam, Abul
    University of Dhaka, Bangladesh.
    Caizzi, Livia
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Di Croce, Luciano
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Nevedomskaya, Ekaterina
    The Netherlands Cancer Institute, Amsterdam.
    Zwart, Wilbert
    The Netherlands Cancer Institute, Amsterdam.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Stockholm South General Hospital, Sweden.
    Sgroi, Dennis C
    Massachusetts General Hospital, Boston, USA.
    Garcia-Mata, Rafael
    University of North Carolina at Chapel Hill, USA.
    Jansen, Maurice Phm
    Cancer Institute, Rotterdam, The Netherlands.
    García, Nadia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Bonifaci, Núria
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Climent, Fina
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Soler, María Teresa
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Vida, Alejo
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gil, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Brunet, Joan
    Hospital Josep Trueta, Girona, Catalonia, Spain.
    Martrat, Griselda
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gómez-Baldó, Laia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Extremera, Ana I
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Figueras, Agnes
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Balart, Josep
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Clarke, Robert
    Georgetown University Medical Center, Washington, DC, USA.
    Burnstein, Kerry L
    University of Miami, Miller School of Medicine, Miami, FL, USA.
    Carlson, Kathryn E
    University of Illinois, Urbana, USA.
    Katzenellenbogen, John A
    University of Illinois, Urbana, USA.
    Vizoso, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Esteller, Manel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain .
    Villanueva, Alberto
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Peña, Ana B
    CSIC-University of Salamanca, Spain.
    Bustelo, Xosé R
    CSIC-University of Salamanca, Spain.
    Nakamura, Yusuke
    University of Tokyo, Japan.
    Zembutsu, Hitoshi
    University of Tokyo, Japan.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Beijersbergen, Roderick L
    The Netherlands Cancer Institute, Amsterdam .
    Pujana, Miguel Angel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    VAV3 mediates resistance to breast cancer endocrine therapy2014In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, no 3, p. R53-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.

    METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.

    RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.

    CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

  • 2. Antoniou, Antonis C.
    et al.
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Beesley, Jonathan
    Chen, Xiaoqing
    McGuffog, Lesley
    Lee, Andrew
    Barrowdale, Daniel
    Healey, Sue
    Sinilnikova, Olga M.
    Caligo, Maria A.
    Loman, Niklas
    Harbst, Katja
    Lindblom, Annika
    Arver, Brita
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Karlsson, Per
    Nathanson, Kate
    Domchek, Susan
    Rebbeck, Tim
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Zlowowcka-Perlowska, Elzbieta
    Osorio, Ana
    Duran, Mercedes
    Andres, Raquel
    Benitez, Javier
    Hamann, Ute
    Hogervorst, Frans B.
    van Os, Theo A.
    Verhoef, Senno
    Meijers-Heijboer, Hanne E. J.
    Wijnen, Juul
    Garcia, Encarna B. Gomez
    Ligtenberg, Marjolijn J.
    Kriege, Mieke
    Collee, Margriet
    Ausems, Margreet G. E. M.
    Oosterwijk, Jan C.
    Peock, Susan
    Frost, Debra
    Ellis, Steve D.
    Platte, Radka
    Fineberg, Elena
    Evans, D. Gareth
    Lalloo, Fiona
    Jacobs, Chris
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Douglas, Fiona
    Brewer, Carole
    Hodgson, Shirley
    Morrison, Patrick J.
    Walker, Lisa
    Rogers, Mark T.
    Donaldson, Alan
    Dorkins, Huw
    Godwin, Andrew K.
    Bove, Betsy
    Stoppa-Lyonnet, Dominique
    Houdayer, Claude
    Buecher, Bruno
    de Pauw, Antoine
    Mazoyer, Sylvie
    Calender, Alain
    Leone, Melanie
    Bressac-de Paillerets, Brigitte
    Caron, Olivier
    Sobol, Hagay
    Frenay, Marc
    Prieur, Fabienne
    Ferrer, Sandra Fert
    Mortemousque, Isabelle
    Buys, Saundra
    Daly, Mary
    Miron, Alexander
    Terry, Mary Beth
    Hopper, John L.
    John, Esther M.
    Southey, Melissa
    Goldgar, David
    Singer, Christian F.
    Fink-Retter, Anneliese
    Tea, Muy-Kheng
    Kaulich, Daphne Geschwantler
    Hansen, Thomas V. O.
    Nielsen, Finn C.
    Barkardottir, Rosa B.
    Gaudet, Mia
    Kirchhoff, Tomas
    Joseph, Vijai
    Dutra-Clarke, Ana
    Offit, Kenneth
    Piedmonte, Marion
    Kirk, Judy
    Cohn, David
    Hurteau, Jean
    Byron, John
    Fiorica, James
    Toland, Amanda E.
    Montagna, Marco
    Oliani, Cristina
    Imyanitov, Evgeny
    Isaacs, Claudine
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Teule, Alex
    Del Valle, J.
    Gayther, Simon A.
    Odunsi, Kunle
    Gross, Jenny
    Karlan, Beth Y.
    Olah, Edith
    Teo, Soo-Hwang
    Ganz, Patricia A.
    Beattie, Mary S.
    Dorfling, Cecelia M.
    van Rensburg, Elizabeth Jansen
    Diez, Orland
    Kwong, Ava
    Schmutzler, Rita K.
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Heidemann, Simone
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorothea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Fiebig, Britta
    Schaefer, Dieter
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Muranen, Taru A.
    Lesperance, Bernard
    Spurdle, Amanda B.
    Neuhausen, Susan L.
    Ding, Yuan C.
    Wang, Xianshu
    Fredericksen, Zachary
    Pankratz, Vernon S.
    Lindor, Noralane M.
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Bonanni, Bernardo
    Bernard, Loris
    Dolcetti, Riccardo
    Papi, Laura
    Ottini, Laura
    Radice, Paolo
    Greene, Mark H.
    Loud, Jennifer T.
    Andrulis, Irene L.
    Ozcelik, Hilmi
    Mulligan, Anna Marie
    Glendon, Gord
    Thomassen, Mads
    Gerdes, Anne-Marie
    Jensen, Uffe B.
    Skytte, Anne-Bine
    Kruse, Torben A.
    Chenevix-Trench, Georgia
    Couch, Fergus J.
    Simard, Jacques
    Easton, Douglas F.
    Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, p. R33-Article in journal (Refereed)
    Abstract [en]

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

    Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

    Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

    Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

  • 3. Arason, Adalgeir
    et al.
    Gunnarsson, Haukur
    Johannesdottir, Gudrun
    Jonasson, Kristjan
    Bendahl, Pär-Ola
    Gillanders, Elizabeth M
    Agnarsson, Bjarni A
    Jönsson, Göran
    Pylkäs, Katri
    Mustonen, Aki
    Heikkinen, Tuomas
    Aittomäki, Kristiina
    Blomqvist, Carl
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johannsson, Oskar TH
    Møller, Pål
    Winqvist, Robert
    Nevanlinna, Heli
    Borg, Åke
    Barkardottir, Rosa B
    Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families2010In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, no 4, p. R50-Article in journal (Refereed)
    Abstract [en]

    Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.

  • 4. Bhoo-Pathy, Nirmala
    et al.
    Peeters, Petra H. M.
    Uiterwaal, Cuno S. P. M.
    Bueno-de-Mesquita, H. Bas
    Bulgiba, Awang M.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Perquier, Florence
    Teucher, Birgit
    Kaaks, Rudolf
    Schuetze, Madlen
    Boeing, Heiner
    Lagiou, Pagona
    Orfanos, Philippos
    Trichopoulou, Antonia
    Agnoli, Claudia
    Mattiello, Amalia
    Palli, Domenico
    Tumino, Rosario
    Sacerdote, Carlotta
    van Duijnhoven, Franzel J. B.
    Braaten, Tonje
    Lund, Eiliv
    Skeie, Guri
    Redondo, Maria-Luisa
    Buckland, Genevieve
    Sanchez Perez, Maria Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Amiano, Pilar
    Wirfalt, Elisabet
    Wallstrom, Peter
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E.
    Key, Timothy J.
    Rinaldi, Sabina
    Romieu, Isabelle
    Gallo, Valentina
    Riboli, Elio
    van Gils, Carla H.
    Coffee and tea consumption and risk of pre- and postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 15Article in journal (Refereed)
    Abstract [en]

    Introduction: Specific coffee subtypes and tea may impact risk of pre- and post-menopausal breast cancer differently. We investigated the association between coffee (total, caffeinated, decaffeinated) and tea intake and risk of breast cancer. Methods: A total of 335,060 women participating in the European Prospective Investigation into Nutrition and Cancer (EPIC) Study, completed a dietary questionnaire from 1992 to 2000, and were followed-up until 2010 for incidence of breast cancer. Hazard ratios (HR) of breast cancer by country-specific, as well as cohort-wide categories of beverage intake were estimated. Results: During an average follow-up of 11 years, 1064 premenopausal, and 9134 postmenopausal breast cancers were diagnosed. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer: adjusted HR = 0.90, 95% confidence interval (CI): 0.82 to 0.98, for high versus low consumption; P-trend = 0.029. While there was no significant effect modification by hormone receptor status (P = 0.711), linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for estrogen and progesterone receptor negative (ER-PR-), postmenopausal breast cancer (P = 0.008). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower by 4% (adjusted HR: 0.96, 95% CI: 0.93 to 1.00). Non-consumers of decaffeinated coffee had lower risk of postmenopausal breast cancer (adjusted HR = 0.89; 95% CI: 0.80 to 0.99) compared to low consumers, without evidence of dose-response relationship (P-trend = 0.128). Exclusive decaffeinated coffee consumption was not related to postmenopausal breast cancer risk, compared to any decaffeinated-low caffeinated intake (adjusted HR = 0.97; 95% CI: 0.82 to 1.14), or to no intake of any coffee (HR: 0.96; 95%: 0.82 to 1.14). Caffeinated and decaffeinated coffee were not associated with premenopausal breast cancer. Tea intake was neither associated with pre- nor post-menopausal breast cancer. Conclusions: Higher caffeinated coffee intake may be associated with lower risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with breast cancer.

  • 5. Blein, Sophie
    et al.
    Bardel, Claire
    Danjean, Vincent
    McGuffog, Lesley
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Dennis, Joe
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Terry, Mary Beth
    Chung, Wendy K.
    Goldgar, David E.
    Buys, Saundra S.
    Janavicius, Ramunas
    Tihomirova, Laima
    Tung, Nadine
    Dorfling, Cecilia M.
    van Rensburg, Elizabeth J.
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Gerdes, Anne-Marie
    Ejlertsen, Bent
    Nielsen, Finn C.
    Hansen, Thomas V. O.
    Osorio, Ana
    Benitez, Javier
    Andres Conejero, Raquel
    Segota, Ena
    Weitzel, Jeffrey N.
    Thelander, Margo
    Peterlongo, Paolo
    Radice, Paolo
    Pensotti, Valeria
    Dolcetti, Riccardo
    Bonanni, Bernardo
    Peissel, Bernard
    Zaffaroni, Daniela
    Scuvera, Giulietta
    Manoukian, Siranoush
    Varesco, Liliana
    Capone, Gabriele L.
    Papi, Laura
    Ottini, Laura
    Yannoukakos, Drakoulis
    Konstantopoulou, Irene
    Garber, Judy
    Hamann, Ute
    Donaldson, Alan
    Brady, Angela
    Brewer, Carole
    Foo, Claire
    Evans, D. Gareth
    Frost, Debra
    Eccles, Diana
    Douglas, Fiona
    Cook, Jackie
    Adlard, Julian
    Barwell, Julian
    Walker, Lisa
    Izatt, Louise
    Side, Lucy E.
    Kennedy, M. John
    Tischkowitz, Marc
    Rogers, Mark T.
    Porteous, Mary E.
    Morrison, Patrick J.
    Platte, Radka
    Eeles, Ros
    Davidson, Rosemarie
    Hodgson, Shirley
    Cole, Trevor
    Godwin, Andrew K.
    Isaacs, Claudine
    Claes, Kathleen
    De Leeneer, Kim
    Meindl, Alfons
    Gehrig, Andrea
    Wappenschmidt, Barbara
    Sutter, Christian
    Engel, Christoph
    Niederacher, Dieter
    Steinemann, Doris
    Plendl, Hansjoerg
    Kast, Karin
    Rhiem, Kerstin
    Ditsch, Nina
    Arnold, Norbert
    Varon-Mateeva, Raymonda
    Schmutzler, Rita K.
    Preisler-Adams, Sabine
    Markov, Nadja Bogdanova
    Wang-Gohrke, Shan
    de Pauw, Antoine
    Lefol, Cedrick
    Lasset, Christine
    Leroux, Dominique
    Rouleau, Etienne
    Damiola, Francesca
    Dreyfus, Helene
    Barjhoux, Laure
    Golmard, Lisa
    Uhrhammer, Nancy
    Bonadona, Valerie
    Sornin, Valerie
    Bignon, Yves-Jean
    Carter, Jonathan
    Van Le, Linda
    Piedmonte, Marion
    DiSilvestro, Paul A.
    de la Hoya, Miguel
    Caldes, Trinidad
    Nevanlinna, Heli
    Aittomaki, Kristiina
    Jager, Agnes
    van den Ouweland, Ans M. W.
    Kets, Carolien M.
    Aalfs, Cora M.
    van Leeuwen, Flora E.
    Hogervorst, Frans B. L.
    Meijers-Heijboer, Hanne E. J.
    Oosterwijk, Jan C.
    van Roozendaal, Kees E. P.
    Rookus, Matti A.
    Devilee, Peter
    van der Luijt, Rob B.
    Olah, Edith
    Diez, Orland
    Teule, Alex
    Lazaro, Conxi
    Blanco, Ignacio
    Del Valle, Jesus
    Jakubowska, Anna
    Sukiennicki, Grzegorz
    Gronwald, Jacek
    Lubinski, Jan
    Durda, Katarzyna
    Jaworska-Bieniek, Katarzyna
    Agnarsson, Bjarni A.
    Maugard, Christine
    Amadori, Alberto
    Montagna, Marco
    Teixeira, Manuel R.
    Spurdle, Amanda B.
    Foulkes, William
    Olswold, Curtis
    Lindor, Noralane M.
    Pankratz, Vernon S.
    Szabo, Csilla I.
    Lincoln, Anne
    Jacobs, Lauren
    Corines, Marina
    Robson, Mark
    Vijai, Joseph
    Berger, Andreas
    Fink-Retter, Anneliese
    Singer, Christian F.
    Rappaport, Christine
    Kaulich, Daphne Geschwantler
    Pfeiler, Georg
    Tea, Muy-Kheng
    Greene, Mark H.
    Mai, Phuong L.
    Rennert, Gad
    Imyanitov, Evgeny N.
    Mulligan, Anna Marie
    Glendon, Gord
    Andrulis, Irene L.
    Tchatchou, Sandrine
    Toland, Amanda Ewart
    Pedersen, Inge Sokilde
    Thomassen, Mads
    Kruse, Torben A.
    Jensen, Uffe Birk
    Caligo, Maria A.
    Friedman, Eitan
    Zidan, Jamal
    Laitman, Yael
    Lindblom, Annika
    Melin, Beatrice
    Arver, Brita
    Loman, Niklas
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Olopade, Olufunmilayo I.
    Nussbaum, Robert L.
    Ramus, Susan J.
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rebbeck, Timothy R.
    Arun, Banu K.
    Mitchell, Gillian
    Karlan, Beth Y.
    Lester, Jenny
    Orsulic, Sandra
    Stoppa-Lyonnet, Dominique
    Thomas, Gilles
    Simard, Jacques
    Couch, Fergus J.
    Offit, Kenneth
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Mazoyer, Sylvie
    Phelan, Catherine M.
    Sinilnikova, Olga M.
    Cox, David G.
    An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 61Article in journal (Refereed)
    Abstract [en]

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

  • 6. Blein, Sophie
    et al.
    Bardel, Claire
    Danjean, Vincent
    McGuffog, Lesley
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Dennis, Joe
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Terry, Mary Beth
    Chung, Wendy K.
    Goldgar, David E.
    Buys, Saundra S.
    Janavicius, Ramunas
    Tihomirova, Laima
    Tung, Nadine
    Dorfling, Cecilia M.
    van Rensburg, Elizabeth J.
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Gerdes, Anne-Marie
    Ejlertsen, Bent
    Nielsen, Finn C.
    Hansen, Thomas V. O.
    Osorio, Ana
    Benitez, Javier
    Andres Conejero, Raquel
    Segota, Ena
    Weitzel, Jeffrey N.
    Thelander, Margo
    Peterlongo, Paolo
    Radice, Paolo
    Pensotti, Valeria
    Dolcetti, Riccardo
    Bonanni, Bernardo
    Peissel, Bernard
    Zaffaroni, Daniela
    Scuvera, Giulietta
    Manoukian, Siranoush
    Varesco, Liliana
    Capone, Gabriele L.
    Papi, Laura
    Ottini, Laura
    Yannoukakos, Drakoulis
    Konstantopoulou, Irene
    Garber, Judy
    Hamann, Ute
    Donaldson, Alan
    Brady, Angela
    Brewer, Carole
    Foo, Claire
    Evans, D. Gareth
    Frost, Debra
    Eccles, Diana
    Douglas, Fiona
    Cook, Jackie
    Adlard, Julian
    Barwell, Julian
    Walker, Lisa
    Izatt, Louise
    Side, Lucy E.
    Kennedy, M. John
    Tischkowitz, Marc
    Rogers, Mark T.
    Porteous, Mary E.
    Morrison, Patrick J.
    Platte, Radka
    Eeles, Ros
    Davidson, Rosemarie
    Hodgson, Shirley
    Cole, Trevor
    Godwin, Andrew K.
    Isaacs, Claudine
    Claes, Kathleen
    De Leeneer, Kim
    Meindl, Alfons
    Gehrig, Andrea
    Wappenschmidt, Barbara
    Sutter, Christian
    Engel, Christoph
    Niederacher, Dieter
    Steinemann, Doris
    Plendl, Hansjoerg
    Kast, Karin
    Rhiem, Kerstin
    Ditsch, Nina
    Arnold, Norbert
    Varon-Mateeva, Raymonda
    Schmutzler, Rita K.
    Preisler-Adams, Sabine
    Markov, Nadja Bogdanova
    Wang-Gohrke, Shan
    de Pauw, Antoine
    Lefol, Cedrick
    Lasset, Christine
    Leroux, Dominique
    Rouleau, Etienne
    Damiola, Francesca
    Dreyfus, Helene
    Barjhoux, Laure
    Golmard, Lisa
    Uhrhammer, Nancy
    Bonadona, Valerie
    Sornin, Valerie
    Bignon, Yves-Jean
    Carter, Jonathan
    Van Le, Linda
    Piedmonte, Marion
    DiSilvestro, Paul A.
    de la Hoya, Miguel
    Caldes, Trinidad
    Nevanlinna, Heli
    Aittomaki, Kristiina
    Jager, Agnes
    van den Ouweland, Ans M. W.
    Kets, Carolien M.
    Aalfs, Cora M.
    van Leeuwen, Flora E.
    Hogervorst, Frans B. L.
    Meijers-Heijboer, Hanne E. J.
    Oosterwijk, Jan C.
    van Roozendaal, Kees E. P.
    Rookus, Matti A.
    Devilee, Peter
    van der Luijt, Rob B.
    Olah, Edith
    Diez, Orland
    Teule, Alex
    Lazaro, Conxi
    Blanco, Ignacio
    Del Valle, Jesus
    Jakubowska, Anna
    Sukiennicki, Grzegorz
    Gronwald, Jacek
    Lubinski, Jan
    Durda, Katarzyna
    Jaworska-Bieniek, Katarzyna
    Agnarsson, Bjarni A.
    Maugard, Christine
    Amadori, Alberto
    Montagna, Marco
    Teixeira, Manuel R.
    Spurdle, Amanda B.
    Foulkes, William
    Olswold, Curtis
    Lindor, Noralane M.
    Pankratz, Vernon S.
    Szabo, Csilla I.
    Lincoln, Anne
    Jacobs, Lauren
    Corines, Marina
    Robson, Mark
    Vijai, Joseph
    Berger, Andreas
    Fink-Retter, Anneliese
    Singer, Christian F.
    Rappaport, Christine
    Kaulich, Daphne Geschwantler
    Pfeiler, Georg
    Tea, Muy-Kheng
    Greene, Mark H.
    Mai, Phuong L.
    Rennert, Gad
    Imyanitov, Evgeny N.
    Mulligan, Anna Marie
    Glendon, Gord
    Andrulis, Irene L.
    Tchatchou, Sandrine
    Toland, Amanda Ewart
    Pedersen, Inge Sokilde
    Thomassen, Mads
    Kruse, Torben A.
    Jensen, Uffe Birk
    Caligo, Maria A.
    Friedman, Eitan
    Zidan, Jamal
    Laitman, Yael
    Lindblom, Annika
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Arver, Brita
    Loman, Niklas
    Rosenquist, Richard
    Olopade, Olufunmilayo I.
    Nussbaum, Robert L.
    Ramus, Susan J.
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rebbeck, Timothy R.
    Arun, Banu K.
    Mitchell, Gillian
    Karlan, Beth Y.
    Lester, Jenny
    Orsulic, Sandra
    Stoppa-Lyonnet, Dominique
    Thomas, Gilles
    Simard, Jacques
    Couch, Fergus J.
    Offit, Kenneth
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Mazoyer, Sylvie
    Phelan, Catherine M.
    Sinilnikova, Olga M.
    Cox, David G.
    An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 61Article in journal (Refereed)
    Abstract [en]

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

  • 7. Borgquist, Signe
    et al.
    Jögi, Annika
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rydén, Lisa
    Brennan, Donal J
    Jirström, Karin
    Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer2008In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 10, no 5, p. R79-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up. METHODS: The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS). RESULTS: In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours. CONCLUSIONS: HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.

  • 8. Brennan, Donal J.
    et al.
    Laursen, Henriette
    O'Connor, Darran P.
    Borgquist, Signe
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Gallagher, William M.
    Ponten, Fredrik
    Millikan, Robert C.
    Ryden, Lisa
    Jirström, Karin
    Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 1, p. R12-Article in journal (Refereed)
    Abstract [en]

    Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. Conclusions: HMG CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.

  • 9. Brennan, Donal J.
    et al.
    Laursen, Henriette
    O'Connor, Darran P.
    Borgquist, Signe
    Uhlén, Mathias
    Gallagher, William M.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Millikan, Robert C.
    Rydén, Lisa
    Jirström, Karin
    Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 1, p. R12-Article in journal (Refereed)
    Abstract [en]

    Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. Conclusions: HMG CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.

  • 10. Campa, Daniele
    et al.
    Barrdahl, Myrto
    Gaudet, Mia M.
    Black, Amanda
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Haiman, Christopher
    Hankinson, Susan
    Hazra, Aditi
    Henderson, Brian
    Hoover, Robert N.
    Hunter, David J.
    Joshi, Amit D.
    Kraft, Peter
    Le Marchand, Loic
    Lindstrom, Sara
    Willett, Walter
    Travis, Ruth C.
    Amiano, Pilar
    Siddiq, Afshan
    Trichopoulos, Dimitrios
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tjonneland, Anne
    Weiderpass, Elisabete
    Peeters, Petra H.
    Panico, Salvatore
    Dossus, Laure
    Ziegler, Regina G.
    Canzian, Federico
    Kaaks, Rudolf
    Genetic risk variants associated with in situ breast cancer2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 82Article in journal (Refereed)
    Abstract [en]

    Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.

    Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.

    Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.

    Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

  • 11.
    Campbell, Diahnn
    et al.
    University of Calif San Diego, CA 92093 USA.
    Saenz, Rebecca
    University of Calif San Diego, CA 92093 USA.
    Bharati, Ila S.
    University of Calif San Diego, CA 92093 USA.
    Seible, Daniel
    University of Calif San Diego, CA 92093 USA.
    Zhang, Liangfang
    University of Calif San Diego, CA 92093 USA.
    Esener, Sadik
    University of Calif San Diego, CA 92093 USA.
    Messmer, Bradley
    University of Calif San Diego, CA 92093 USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of Calif San Diego, CA 92093 USA.
    Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D, L-lactic-co-glycolic) acid nanoparticles nanoparticles2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, no 48Article in journal (Refereed)
    Abstract [en]

    Introduction Cancer vaccines have the potential to induce curative anti-tumor immune responses and better adjuvants may improve vaccine efficacy. We have previously shown that Hp91, a peptide derived from the B box domain in high-mobility group box protein 1 (HMGB1), acts as potent immune adjuvant. Method In this study, Hp91 was tested as part of a therapeutic vaccine against human epidermal growth factor receptor 2 (HER2) positive breast cancer. Results Free peptide did not significantly augment immune responses but, when delivered in poly(D, L-lactic-co-glycolic) acid nanoparticles (PLGA-NPs), robust activation of dendritic cells (DCs) and increased activation of HER2 specific T cells was observed in vitro. Vaccination of HER2NEU transgenic mice, a mouse breast cancer model that closely mimics the immune modulation and tolerance in some breast cancer patients, with Hp91 loaded PLGA-NPs enhanced the activation of HER2 specific cytotoxic T lymphocyte (CTL) responses, delayed tumor development, and prolonged survival. Conclusion Taken together these findings demonstrate that the delivery of the immunostimulatory peptide Hp91 inside PLGA-NPs enhances the potency of the peptide and efficacy of a breast cancer vaccine.

  • 12.
    Drabsch, Yvette
    et al.
    Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300, RC, Leiden, The Nethe.
    He, Shuning
    Institute of Biology, Leiden University, Einsteinweg 55, 2333, CC Leiden, The Netherlands .
    Zhang, Long
    Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300, RC, Leiden, The Nethe.
    Snaar-Jagalska, B Ewa
    Institute of Biology, Leiden University, Einsteinweg 55, 2333, CC Leiden, The Netherlands .
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300, RC, Leiden, The Netherlands .
    Transforming growth factor-β signalling controls human breast cancer metastasis in a zebrafish xenograft model2013In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 6, p. R106-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The transforming growth factor beta (TGF-β) signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-β signalling in human breast tumour cells.

    METHODS: We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-β signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy.

    RESULTS: Breast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-β receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-β in breast cancer cells, blocked invasion and metastasis of breast cancer cells.

    CONCLUSIONS: The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-β drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.

  • 13. Duffy, S
    et al.
    Agbaje, O
    Tabar, L
    Bedrich, Vitak
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Medical Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL.
    Bjurstam, N
    Björneld, L
    Myles, J
    Warwick, J
    Estimates of overdiagnosis from two trials of mammographic screening for breast cancer2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 6, p. 258-265Article in journal (Refereed)
    Abstract [en]

    Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1 % of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1 % of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation. © 2005 BioMed Central Ltd.

  • 14. Heikkinen, Tuomas
    et al.
    Greco, Dario
    Pelttari, Liisa M
    Tommiska, Johanna
    Vahteristo, Pia
    Heikkilä, Päivi
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Variants on the promoter region of PTEN affect breast cancer progression and patient survival2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6, p. R130-Article in journal (Refereed)
    Abstract [en]

    INTRODUTION:

    The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.

    METHODS:

    We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.

    RESULTS:

    All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.

    CONCLUSIONS:

    Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.

  • 15.
    Jerevall, Piiha-Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital.
    Skoog, Lambert
    Department of Clinical Pathology and Cytology, Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer2010In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, no 4Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: INTRODUCTION: The HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression. METHODS: We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment. RESULTS: Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients. CONCLUSIONS: A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.

  • 16.
    Johansson, Ida
    et al.
    Lund University, Sweden.
    Nilsson, Cecilia
    Central Hospital Vasteres, Sweden Uppsala University, Sweden .
    Berglund, Pontus
    Lund University, Sweden .
    Lauss, Martin
    Lund University, Sweden.
    Ringner, Markus
    Lund University, Sweden.
    Olsson, Hakan
    Lund University, Sweden .
    Luts, Lena
    Lund University, Sweden .
    Sim, Edith
    University of Oxford, England .
    Thorstensson, Sten
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fjallskog, Marie-Louise
    Uppsala University, Sweden .
    Hedenfalk, Ingrid
    Lund University, Sweden .
    Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    Introduction: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC). less thanbrgreater than less thanbrgreater thanMethods: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs. less thanbrgreater than less thanbrgreater thanResults: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC. less thanbrgreater than less thanbrgreater thanConclusions: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

  • 17.
    Johansson, Ida
    et al.
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
    Nilsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Berglund, Pontus
    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Lauss, Martin
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
    Ringner, Markus
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
    Olsson, Håkan
    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Luts, Lena
    Department of pathology, Lund University Hospital, Lund, Sweden.
    Sim, Edith
    Department of Pharmacology, University of Oxford, UK.
    Thorstenson, Sten
    Department of Pathology, Linköping University Hospital, Linköping, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedenfalk, Ingrid
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
    Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, p. R31-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC).

    METHODS:

    A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs.

    RESULTS:

    Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC.

    CONCLUSIONS:

    We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

  • 18.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pérez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Amin, Risul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Stockholm, Sweden .
    Sgroi, Dennis C
    Department of Pathology, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hallbeck, Anna-Lotta
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.2013In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 5, p. R96-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

    METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

    RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

    CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.

  • 19. Li, Yihao
    et al.
    Drabsch, Yvette
    Pujuguet, Philippe
    Ren, Jiang
    van Laar, Theo
    Zhang, Long
    van Dam, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clement-Lacroix, Philippe
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic depletion and pharmacological targeting of alpha v integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 28Article in journal (Refereed)
    Abstract [en]

    Introduction: Increased expression of alpha v integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which alpha v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of alpha v integrins in breast cancer also have yet to be investigated. Methods: We knocked down alpha v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the alpha v antagonist GLPG0187. The effects of alpha v integrin depletion on mesenchymal markers, transforming growth factor-beta (TGF-beta)/Smad signaling and TGF-beta-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of alpha v integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis. Results: Genetic interference and pharmacological targeting of alpha v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of alpha v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-beta/Smad response. TGF-beta induced alpha v integrin mRNA expression and alpha v integrin was required for TGF-beta-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-beta signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments. Conclusion: These findings show that alpha v integrin is required for efficient TGF-beta/Smad signaling and TGF-beta-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting alpha v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress alpha v integrin.

  • 20.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer2009In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 11, no 3, p. 403-Article in journal (Refereed)
  • 21.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Thomasson, Marcus
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Höckenström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Emdin, Stefan
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Jonsson, Yvonne
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Increased copy number at 3p14 in breast cancer2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 5, p. R719-R727Article in journal (Refereed)
  • 22. Martrat, Griselda
    et al.
    Maxwell, Christopher A.
    Tominaga, Emiko
    Porta-de-la-Riva, Montserrat
    Bonifaci, Nuria
    Gomez-Baldo, Laia
    Bogliolo, Massimo
    Lazaro, Conxi
    Blanco, Ignacio
    Brunet, Joan
    Aguilar, Helena
    Fernandez-Rodriguez, Juana
    Seal, Sheila
    Renwick, Anthony
    Rahman, Nazneen
    Kuehl, Julia
    Neveling, Kornelia
    Schindler, Detlev
    Ramirez, Maria J.
    Castella, Maria
    Hernandez, Gonzalo
    Easton, Douglas F.
    Peock, Susan
    Cook, Margaret
    Oliver, Clare T.
    Frost, Debra
    Platte, Radka
    Evans, D. Gareth
    Lalloo, Fiona
    Eeles, Rosalind
    Izatt, Louise
    Chu, Carol
    Davidson, Rosemarie
    Ong, Kai-Ren
    Cook, Jackie
    Douglas, Fiona
    Hodgson, Shirley
    Brewer, Carole
    Morrison, Patrick J.
    Porteous, Mary
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Roversi, Gaia
    Barile, Monica
    Viel, Alessandra
    Pasini, Barbara
    Ottini, Laura
    Putignano, Anna Laura
    Savarese, Antonella
    Bernard, Loris
    Radice, Paolo
    Healey, Sue
    Spurdle, Amanda
    Chen, Xiaoqing
    Beesley, Jonathan
    Rookus, Matti A.
    Verhoef, Senno
    Tilanus-Linthorst, Madeleine A.
    Vreeswijk, Maaike P.
    Asperen, Christi J.
    Bodmer, Danielle
    Ausems, Margreet G. E. M.
    van Os, Theo A.
    Blok, Marinus J.
    Meijers-Heijboer, Hanne E. J.
    Hogervorst, Frans B. L.
    Goldgar, David E.
    Buys, Saundra
    John, Esther M.
    Miron, Alexander
    Southey, Melissa
    Daly, Mary B.
    Harbst, Katja
    Borg, Ake
    Rantala, Johanna
    Barbany-Bustinza, Gisela
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stenmark-Askmalm, Marie
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Friedman, Eitan
    Domchek, Susan M.
    Nathanson, Katherine L.
    Rebbeck, Timothy R.
    Johannsson, Oskar Thor
    Couch, Fergus J.
    Wang, Xianshu
    Fredericksen, Zachary
    Cuadras, Daniel
    Moreno, Vctor
    Pientka, Friederike K.
    Depping, Reinhard
    Caldes, Trinidad
    Osorio, Ana
    Benitez, Javier
    Bueren, Juan
    Heikkinen, Tuomas
    Nevanlinna, Heli
    Hamann, Ute
    Torres, Diana
    Caligo, Maria Adelaide
    Godwin, Andrew K.
    Imyanitov, Evgeny N.
    Janavicius, Ramunas
    Sinilnikova, Olga M.
    Stoppa-Lyonnet, Dominique
    Mazoyer, Sylvie
    Verny-Pierre, Carole
    Castera, Laurent
    de Pauw, Antoine
    Bignon, Yves-Jean
    Uhrhammer, Nancy
    Peyrat, Jean-Philippe
    Vennin, Philippe
    Ferrer, Sandra Fert
    Collonge-Rame, Marie-Agnes
    Mortemousque, Isabelle
    McGuffog, Lesley
    Chenevix-Trench, Georgia
    Pereira-Smith, Olivia M.
    Antoniou, Antonis C.
    Ceron, Julian
    Tominaga, Kaoru
    Surralles, Jordi
    Angel Pujana, Miguel
    Exploring the link between MORF4L1 and risk of breast cancer2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 2, p. R40-Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

  • 23.
    Martrat, Griselda
    et al.
    IDIBELL.
    Maxwell, Christopher A.
    IDIBELL.
    Tominaga, Emiko
    University of Texas Health Science Centre San Antonio.
    Porta-de-la-Riva, Montserrat
    Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, IDIBELL, Spain.
    Bonifaci, Nuria
    IDIBELL.
    Gomez-Baldo, Laia
    IDIBELL.
    Bogliolo, Massimo
    Autonomous University Barcelona.
    Lazaro, Conxi
    IDIBELL.
    Blanco, Ignacio
    IDIBELL.
    Brunet, Joan
    Hospital Josep Trueta.
    Aguilar, Helena
    Bellvitge Institute Biomed Research IDIBELL.
    Fernandez-Rodriguez, Juana
    IDIBELL.
    Seal, Sheila
    Institute Canc Research.
    Renwick, Anthony
    Institute Canc Research.
    Rahman, Nazneen
    Institute Canc Research.
    Küehl, Julia
    Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, Würzburg, Germany .
    Neveling, Kornelia
    University Wurzburg.
    Schindler, Detlev
    University Wurzbur.
    J. Ramirez, Maria
    Autonomous University Barcelona.
    Castella, Maria
    Autonomous University Barcelon.
    Hernandez, Gonzalo
    Autonomous University Barcelona.
    F. Easton, Douglas
    University Cambridge.
    Peock, Susan
    University Cambridge.
    Cook, Margaret
    University Cambridge.
    T. Oliver, Clare
    University Cambridge.
    Frost, Debra
    University Cambridge.
    Platte, Radka
    University Cambridge.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust.
    Eeles, Rosalind
    Institute Canc Research, Oncogenet Team.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Chu, Carol
    St James Hospital.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet.
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare NHS Trust.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Douglas, Fiona
    Newcastle Upon Tyne Hospital NHS Trust.
    Hodgson, Shirley
    University London.
    Brewer, Carole
    Royal Devon and Exeter Hospital.
    J. Morrison, Patrick
    Belfast City Hospital.
    Porteous, Mary
    Western Gen Hospital.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Manoukian, Siranoush
    Fdn IRCCS INT.
    Peissel, Bernard
    Fdn IRCCS INT.
    Zaffaroni, Daniela
    Fdn IRCCS INT.
    Roversi, Gaia
    Fdn IRCCS INT.
    Barile, Monica
    Ist Europeo Oncol IEO.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University Turin.
    Ottini, Laura
    University Roma La Sapienza.
    Laura Putignano, Anna
    Fiorgen Fdn Pharmacogen.
    Savarese, Antonella
    Regina Elena Institute Canc Research.
    Bernard, Loris
    IEO.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Healey, Sue
    Queensland Institute Med Research.
    Spurdle, Amanda
    Queensland Institute Med Research.
    Chen, Xiaoqing
    Queensland Institute Med Research.
    Beesley, Jonathan
    Queensland Institute Med Research.
    A. Rookus, Matti
    Netherlands Canc Institute.
    Verhoef, Senno
    Netherlands Canc Institute.
    A. Tilanus-Linthorst, Madeleine
    Erasmus MC Daniel den Hoed Canc Centre.
    P. Vreeswijk, Maaike
    Leiden University.
    J. Asperen, Christi
    Leiden University.
    Bodmer, Danielle
    Radboud University Nijmegen.
    G. E. M. Ausems, Margreet
    University Med Centre Utrecht.
    A. van Os, Theo
    University Amsterdam.
    J. Blok, Marinus
    University Hospital Maastricht.
    E. J. Meijers-Heijboer, Hanne
    Vrije University Amsterdam Med Centre.
    B. L. Hogervorst, Frans
    Netherlands Canc Institute.
    E. Goldgar, David
    University Utah.
    Buys, Saundra
    Huntsman Canc Institute.
    M. John, Esther
    Canc Prevent Institute Calif.
    Miron, Alexander
    Harvard University.
    Southey, Melissa
    University Melbourne.
    B. Daly, Mary
    Fox Chase Canc Centre.
    Harbst, Katja
    Skane University Hospital.
    Borg, Ake
    Skane University Hospital.
    Rantala, Johanna
    Karolinska University Hospital.
    Barbany-Bustinza, Gisela
    Karolinska University Hospital.
    Ehrencrona, Hans
    Uppsala University.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Kaufman, Bella
    The Institute of Oncology, Chaim Sheba Medical Center, Israel .
    Laitman, Yael
    Chaim Sheba Med Centre.
    Milgrom, Roni
    Chaim Sheba Med Centre.
    Friedman, Eitan
    Chaim Sheba Med Centre.
    M. Domchek, Susan
    University Penn.
    L. Nathanson, Katherine
    University Penn.
    R. Rebbeck, Timothy
    University Penn.
    Thor Johannsson, Oskar
    Department of Oncology, 20A Landspitali-LSH v/Hringbraut, Reykjavik, Iceland.
    J. Couch, Fergus
    Mayo Clin.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    Cuadras, Daniel
    IDIBELL.
    Moreno, Vctor
    IDIBELL.
    K. Pientka, Friederike
    University Lubeck.
    Depping, Reinhard
    University Lubeck.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    Osorio, Ana
    Spanish Natl Canc Research Centre.
    Benitez, Javier
    Spanish Natl Canc Research Centre.
    Bueren, Juan
    Centre Invest Energet Medioambientales and Tecnol CIEM,.
    Heikkinen, Tuomas
    University Helsinki.
    Nevanlinna, Heli
    University Helsinki.
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ.
    Torres, Diana
    Pontificia University Javeriana.
    Adelaide Caligo, Maria
    University Hospital Pisa.
    K. Godwin, Andrew
    University Kansas.
    N. Imyanitov, Evgeny
    NN Petrov Oncol Research Institute.
    Janavicius, Ramunas
    Vilnius University Hospital.
    M. Sinilnikova, Olga
    University Lyon 1.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Mazoyer, Sylvie
    University Lyon 1.
    Verny-Pierre, Carole
    University Lyon 1.
    Castera, Laurent
    Institute Curie.
    de Pauw, Antoine
    Institute Curie.
    Bignon, Yves-Jean
    University Clermont Ferrand.
    Uhrhammer, Nancy
    University Clermont Ferrand.
    Peyrat, Jean-Philippe
    Centre Oscar Lambret.
    Vennin, Philippe
    Consultation d'Oncogénétique, Centre Oscar Lambret, Lille, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital.
    Collonge-Rame, Marie-Agnes
    CHU Besancon.
    Mortemousque, Isabelle
    CHU Bretonneau.
    McGuffog, Lesley
    University Cambridge.
    Chenevix-Trench, Georgia
    Queensland Institute Med Research.
    M. Pereira-Smith, Olivia
    University Texas Hlth Science Centre San Antonio.
    C. Antoniou, Antonis
    University Cambridge.
    Ceron, Julian
    IDIBELL.
    Tominaga, Kaoru
    University Texas Hlth Science Centre San Antonio.
    Surralles, Jordi
    Autonomous University Barcelona.
    Angel Pujana, Miguel
    Catalan Institute of Oncology, IDIBELL, Spain.
    Exploring the link between MORF4L1 and risk of breast cancer2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 2Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

  • 24.
    Monazzam, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Josephsson, Raymond
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer2007In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 9, no 4, p. R45-Article in journal (Refereed)
    Abstract [en]

    Introduction

    Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.

    Methods

    MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.

    Results

    The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.

    Conclusion

    SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.

  • 25. Muggerud, Aslaug Aa
    et al.
    Rønneberg, Jo Anders
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Busato, Florence
    Jovanovic, Jovana
    Solvang, Hiroko
    Bukholm, Ida
    Børresen-Dale, Anne-Lise
    Kristensen, Vessela N.
    Sørlie, Therese
    Tost, Jörg
    Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer2010In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, no 1, p. R3-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. METHODS: Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. RESULTS: Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. CONCLUSIONS: Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.

  • 26.
    Mulligan, Anna Marie
    et al.
    University of Toronto.
    Couch, Fergus J
    Rochester.
    Barrowdale, Daniel
    University of Cambridge.
    Domchek, Susan M
    University of Penn.
    Eccles, Diana
    University of Southampton.
    Nevanlinna, Heli
    University of Helsinki.
    Ramus, Susan J
    University of So Calif.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre.
    Sherman, Mark
    NCI.
    Spurdle, Amanda B
    Queensland Institute Medical Research.
    Wappenschmidt, Barbara
    University Hospital Cologne.
    Lee, Andrew
    University of Cambridge.
    McGuffog, Lesley
    University of Cambridge.
    Healey, Sue
    Queensland Institute Medical Research.
    Sinilnikova, Olga M
    Centre Hospital University of Lyon Centre Leon Berard.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin.
    Hansen, Thomas V O
    Copenhagen University Hospital.
    Nielsen, Finn C
    Copenhagen University Hospital.
    Ejlertsen, Bent
    Copenhagen University Hospital, Rigshosp.
    Osorio, Ana
    Spanish National Cancer Research Centre.
    Munoz-Repeto, Ivan
    Spanish National Cancer Research Centre.
    Duran, Mercedes
    University of Valladolid.
    Godino, Javier
    Hospital Clin University of Lozano Blesa.
    Pertesi, Maroulio
    National Centre Science Research Demokritos.
    Benitez, Javier
    Spanish National Cancer Research Centre.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumouri INT.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumouri INT.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumouri INT.
    Cattaneo, Elisa
    Fdn IRCCS Ist Nazl Tumouri INT.
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Cancer Prevent and Genet.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University of Turin.
    Papi, Laura
    University of Florence.
    Ottini, Laura
    University of Roma La Sapienza.
    Savarese, Antonella
    Regina Elena Institute Cancer Research.
    Bernard, Loris
    Ist Europeo Oncol.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Hamann, Ute
    DKFZ.
    Verheus, Martijn
    Netherlands Cancer Institute.
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre.
    Wijnen, Juul
    Leiden University.
    Gomez Garcia, EncarnaB
    MUMC.
    Nelen, Marcel R
    Radboud University of Nijmegen.
    Kets, C Marleen
    Radboud University of Nijmegen.
    Seynaeve, Caroline
    Erasmus University.
    Tilanus-Linthorst, Madeleine M A
    Erasmus University.
    van der Luijt, Rob B
    University of Medical Centre Utrecht.
    van Os, Theo
    University of Amsterdam.
    Rookus, Matti
    Netherlands Cancer Institute.
    Frost, Debra
    University of Cambridge.
    Jones, J Louise
    Queen Mary University of London.
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust.
    Eeles, Ros
    Institute Cancer Research, Oncogenet Team, London.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Adlard, Julian
    Yorkshire Regional Genet Serv.
    Davidson, Rosemarie
    Yorkhill Hospital.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Donaldson, Alan
    St Michaels Hospital.
    Dorkins, Huw
    Kennedy Galton Centre.
    Gregory, Helen
    NHS Grampian.
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust.
    Houghton, Catherine
    Liverpool Womens NHS Fdn Trust.
    Barwell, Julian
    University Hospital Leicester NHS Trust.
    E Side, Lucy
    Great Ormond St Hospital Sick Children.
    McCann, Emma
    Glan Clwyd Gen Hospital.
    Murray, Alex
    Singleton Hospital.
    Peock, Susan
    University of Cambridge.
    K Godwin, Andrew
    University of Kansas.
    K Schmutzler, Rita
    University Hospital Cologne.
    Rhiem, Kerstin
    University Hospital Cologne.
    Engel, Christoph
    University of Leipzig.
    Meindl, Alfons
    Technical University of Munich.
    Ruehl, Ina
    University of Munich.
    Arnold, Norbert
    University of Kiel.
    Niederacher, Dieter
    University of Dusseldorf.
    Sutter, Christian
    University of Heidelberg Hospital.
    Deissler, Helmut
    University Hospital.
    Gadzicki, Dorothea
    Hannover Medical Sch.
    Kast, Karin
    Technical University of Dresden.
    Preisler-Adams, Sabine
    University of Munster.
    Varon-Mateeva, Raymonda
    Charite, Campus Virchov Klinikum.
    Schoenbuchner, Ines
    University of Wurzburg.
    Fiebig, Britta
    University of Regensburg.
    Heinritz, Wolfram
    University of Leipzig.
    Schaefer, Dieter
    University Hospital, Frankfurt.
    Gevensleben, Heidrun
    Institute Cancer Research,London.
    Caux-Moncoutier, Virginie
    Institute Curie .
    Fassy-Colcombet, Marion
    Institute Curie.
    Cornelis, Francois
    Avicenne Hospital.
    Mazoyer, Sylvie
    University of Lyon 1.
    Leone, Melanie
    Centre Hospital University of Lyon Centre Leon Berard.
    Boutry-Kryza, Nadia
    Centre Hospital University of Lyon Centre Leon Berard.
    Hardouin, Agnes
    Centre Francois Baclesse.
    Berthet, Pascaline
    Centre Francois Baclesse.
    Muller, Daniele
    CLCC Paul Strauss.
    Fricker, Jean-Pierre
    CLCC Paul Strauss.
    Mortemousque, Isabelle
    CHU Bretonneau.
    Pujol, Pascal
    CHU Amaud de Villeneuve.
    Coupier, Isabelle
    CHU Amaud de Villeneuve.
    Lebrun, Marine
    Centre Hospital University of St Etienne.
    Kientz, Caroline
    Centre Hospital University of St Etienne.
    Longy, Michel
    University of Bordeaux.
    Sevenet, Nicolas
    University of Bordeaux.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Isaacs, Claudine
    Georgetown University.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    de la Hoya, Miguel
    Hospital Clin San Carlos.
    Heikkinen, Tuomas
    University of Helsinki.
    Aittomaki, Kristiina
    University of Helsinki.
    Blanco, Ignacio
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    Lazaro, Conxi
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    B Barkardottir, Rosa
    Landspitali University Hospital.
    Soucy, Penny
    CHU Quebec.
    Dumont, Martine
    CHU Quebec.
    Simard, Jacques
    CHU Quebec.
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS.
    Tognazzo, Silvia
    Ist Oncology Veneto IOV IRCCS.
    DAndrea, Emma
    University of Padua.
    Fox, Stephen
    Peter MacCallum Cancer Centre.
    Yan, Max
    Prince Wales Hospital.
    Rebbeck, Tim
    Abramson Cancer Centre.
    I Olopade, Olufunmilayo
    University of Chicago.
    N Weitzel, Jeffrey
    City Hope National Medical Centre.
    T Lynch, Henry
    Creighton University.
    A Ganz, Patricia
    University of Calif Los Angeles.
    E Tomlinson, Gail
    University of Texas SW Medical Centre Dallas.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    S Pankratz, Vernon
    Mayo Clin.
    M Lindor, Noralane
    Mayo Clin.
    Szabo, Csilla
    University of Delaware.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre.
    Sakr, Rita
    Mem Sloan Kettering Cancer Centre.
    Gaudet, Mia
    Amer Cancer Soc.
    Bhatia, Jasmine
    Mem Sloan Kettering Cancer Centre.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre.
    F Singer, Christian
    Medical University of Vienna.
    Tea, Muy-Kheng
    Medical University of Vienna.
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna.
    Fink-Retter, Anneliese
    Medical University of Vienna.
    L Mai, Phuong
    US National Cancer Institute.
    H Greene, Mark
    US National Cancer Institute.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol.
    P OMalley, Frances
    St Michaels Hospital.
    Ozcelik, Hilmi
    Mt Sinai Hospital.
    Glendon, Gordon
    Ohio State University.
    Gerdes, Anne-Marie
    University of Copenhagen.
    Thomassen, Mads
    Odense University Hospital.
    A Kruse, Torben
    Odense University Hospital.
    Birk Jensen, Uffe
    Aarhus University Hospital.
    Skytte, Anne-Bine
    Vejle Hospital.
    A Caligo, Maria
    University of Pisa.
    Soller, Maria
    University of Lund Hospital.
    Henriksson, Karin
    University of Lund Hospital.
    Anna Wachenfeldt, von
    Karolinska University Hospital.
    Arver, Brita
    Karolinska University Hospital.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Karlsson, Per
    Sahlgrens University Hospital.
    Chun Ding, Yuan
    City Hope National Medical Centre.
    L Neuhausen, Susan
    City Hope National Medical Centre.
    Beattie, Mary
    University of Calif San Francisco.
    D P Pharoah, Paul
    University of Cambridge.
    B Moysich, Kirsten
    Roswell Pk Cancer Institute.
    L Nathanson, Katherine
    University of Penn.
    Y Karlan, Beth
    Cedars Sinai Medical Centre.
    Gross, Jenny
    Cedars Sinai Medical Centre.
    M John, Esther
    Cancer Prevent Institute Calif.
    B Daly, Mary
    Fox Chase Cancer Centre.
    M Buys, Saundra
    University of Utah.
    C Southey, Melissa
    University of Melbourne.
    L Hopper, John
    University of Melbourne.
    Beth Terry, Mary
    Columbia University.
    Chung, Wendy
    Columbia University.
    F Miron, Alexander
    Dana Farber Cancer Institute.
    Goldgar, David
    University of Utah.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research.
    F Easton, Douglas
    University of Cambridge.
    L Andrulis, Irene
    University of Toronto.
    C Antoniou, Antonis
    University of Cambridge.
    Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/22011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6Article in journal (Refereed)
    Abstract [en]

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. less thanbrgreater than less thanbrgreater thanMethods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. less thanbrgreater than less thanbrgreater thanResults: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. less thanbrgreater than less thanbrgreater thanConclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

  • 27. O'Leary, Patrick C.
    et al.
    Terrile, Marta
    Bajor, Malgorzata
    Gaj, Pawel
    Hennessy, Bryan T.
    Mills, Gordon B.
    Zagozdzon, Agnieszka
    O'Connor, Darran P.
    Brennan, Donal J.
    Connor, Kate
    Li, Jane
    Gonzalez-Angulo, Ana Maria
    Sun, Han-Dong
    Pu, Jian-Xin
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Uhlen, Mathias
    Jirstrom, Karin
    Nowis, Dominika A.
    Crown, John P.
    Zagozdzon, Radoslaw
    Gallagher, William M.
    Peroxiredoxin-1 protects estrogen receptor alpha from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer2014In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, no 4, p. R79-Article in journal (Refereed)
    Abstract [en]

    Introduction: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. Methods: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. Results: In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ER alpha protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ER alpha protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ER alpha levels in breast cancer cells. Conclusions: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ER alpha loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.

  • 28. O'Leary, Patrick C.
    et al.
    Terrile, Marta
    Bajor, Malgorzata
    Gaj, Pawel
    Hennessy, Bryan T.
    Mills, Gordon B.
    Zagozdzon, Agnieszka
    O'Connor, Darran P.
    Brennan, Donal J.
    Connor, Kate
    Li, Jane
    Gonzalez-Angulo, Ana Maria
    Sun, Han-Dong
    Pu, Jian-Xin
    Pontén, Fredrik
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Jirstrom, Karin
    Nowis, Dominika A.
    Crown, John P.
    Zagozdzon, Radoslaw
    Gallagher, William M.
    Peroxiredoxin-1 protects estrogen receptor alpha from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer2014In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, no 4, p. R79-Article in journal (Refereed)
    Abstract [en]

    Introduction: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. Methods: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. Results: In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ER alpha protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ER alpha protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ER alpha levels in breast cancer cells. Conclusions: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ER alpha loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.

  • 29.
    Palmebäck Wegman, Pia
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Wingren, Sten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    CYP2D6 variants and the prediction of tamoxifen response in randomized patients: authors' response2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 6, p. 234-234Article in journal (Refereed)
  • 30. Scarmo, Stephanie
    et al.
    Afanasyeva, Yelena
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Koenig, Karen L
    Horst, Ronald L
    Clendenen, Tess V
    Arslan, Alan A
    Chen, Yu
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lundin, Eva
    Rinaldi, Sabina
    Toniolo, Paolo
    Shore, Roy E
    Zeleniuch-Jacquotte, Anne
    Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study2013In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 1, p. R15-Article in journal (Refereed)
    Abstract [en]

    Introduction: Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH) D) in breast cancer development, but the results of epidemiological studies have been inconsistent.

    Methods: We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH) D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.

    Results: No association was observed between circulating levels of 25(OH) D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH) D > 0.70). An inverse association between 25(OH) D levels and breast cancer risk was observed among women who were = 45 years of age (ORQ5-Q1 = 0.48, 95% CI = 0.30-0.79, ptrend = 0.01) or premenopausal at enrollment (ORQ5-Q1 = 0.67, 95% CI = 0.48-0.92, ptrend = 0.03).

    Conclusions: Circulating 25(OH) D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention.

  • 31.
    Stål, Olle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Åkerberg, Lind
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, no 2, p. R37-R44Article in journal (Refereed)
    Abstract [en]

    Background

    The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

    Methods

    We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

    Results

    Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

    Conclusion

    Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

  • 32.
    Sundqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    van Dam, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, article id 204Article, review/survey (Refereed)
    Abstract [en]

    Smad proteins are the key intermediates of transforming growth factor-beta (TGF-β) signaling during development and in tissue homeostasis. Pertubations in TGF-β/Smad signaling have been implicated in cancer and other diseases. In the cell nucleus, Smad complexes trigger cell type- and context-specific transcriptional programs, thereby transmitting and integrating signals from a variety of ligands of the TGF-β superfamily and other stimuli in the cell microenvironment. The actual transcriptional and biological outcome of Smad activation critically depends on the genomic integrity and the modification state of genome and chromatin of the cell. The cytoplasmic and nuclear Smads can also modulate the activity of other signal transducers and enzymes such as microRNA-processing factors. In the case of breast cancer, the role of Smads in epithelial plasticity, tumor-stroma interactions, invasion, and metastasis seems of particular importance.

  • 33. Tikk, Kaja
    et al.
    Sookthai, Disorn
    Fortner, Renee T.
    Johnson, Theron
    Rinaldi, Sabina
    Romieu, Isabelle
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Baglietto, Laura
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Krogh, Vittorio
    Tumino, Rosario
    Ricceri, Fulvio
    Mattiello, Amalia
    Agudo, Antonio
    Menendez, Virginia
    Sanchez, Maria-Jose
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Bueno-de-Mesquita, HBas
    Monninkhof, Evelyn M.
    Onland-Moret, N. Charlotte
    Andresson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Weiderpass, Elisabete
    Khaw, Kay-Tee
    Key, Timothy J.
    Travis, Ruth C.
    Merritt, Melissa A.
    Riboli, Elio
    Dossus, Laure
    Kaaks, Rudolf
    Circulating prolactin and in situ breast cancer risk in the European EPIC cohort: a case-control study2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 49Article in journal (Refereed)
    Abstract [en]

    Introduction The relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention.

    Methods We analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer overall, and by menopausal status and use of postmenopausal hormone therapy (HT) at blood donation. Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects.

    Results We found a significant positive association between higher circulating prolactin levels and risk of in situ breast cancer among all women [pre-and postmenopausal combined, ORlog2 = 1.35 (95% CI 1.04-1.76), P-trend = 0.03]. No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (P-het = 0.98) or baseline HT use (P-het = 0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (P-trend = 0.06 vs P-trend = 0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors <4 years compared to >= 4 years after blood donation (P-trend = 0.01 vs P-trend = 0.63; P-het = 0.04) and among nulliparous women compared to parous women (P-trend = 0.03 vs P-trend = 0.15; P-het = 0.07).

    Conclusions Our data extends prior research linking prolactin and invasive breast cancer to the outcome of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.The relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention.

  • 34. Walker, Logan C
    et al.
    Fredericksen, Zachary S
    Wang, Xianshu
    Tarrell, Robert
    Pankratz, Vernon S
    Lindor, Noralane M
    Beesley, Jonathan
    Healey, Sue
    Chen, Xiaoqing
    Stoppa-Lyonnet, Dominique
    Tirapo, Carole
    Giraud, Sophie
    Mazoyer, Sylvie
    Muller, Danièle
    Fricker, Jean-Pierre
    Delnatte, Capucine
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Schönbuchner, Ines
    Deissler, Helmut
    Meindl, Alfons
    Hogervorst, Frans B
    Verheus, Martijn
    Hooning, Maartje J
    van den Ouweland, Ans Mw
    Nelen, Marcel R
    Ausems, Margreet Gem
    Aalfs, Cora M
    van Asperen, Christi J
    Devilee, Peter
    Gerrits, Monique M
    Waisfisz, Quinten
    Szabo, Csilla I
    Easton, Douglas F
    Peock, Susan
    Cook, Margaret
    Oliver, Clare T
    Frost, Debra
    Harrington, Patricia
    Evans, D Gareth
    Lalloo, Fiona
    Eeles, Ros
    Izatt, Louise
    Chu, Carol
    Davidson, Rosemarie
    Eccles, Diana
    Ong, Kai-Ren
    Cook, Jackie
    Rebbeck, Tim
    Nathanson, Katherine L
    Domchek, Susan M
    Singer, Christian F
    Gschwantler-Kaulich, Daphne
    Dressler, Anne-Catharina
    Pfeiler, Georg
    Godwin, Andrew K
    Heikkinen, Tuomas
    Nevanlinna, Heli
    Agnarsson, Bjarni A
    Caligo, Maria Adelaide
    Olsson, Håkan
    Kristoffersson, Ulf
    Liljegren, Annelie
    Arver, Brita
    Karlsson, Per
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sinilnikova, Olga M
    McGuffog, Lesley
    Antoniou, Antonis C
    Chenevix-Trench, Georgia
    Spurdle, Amanda B
    Couch, Fergus J
    Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers2010In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, no 6, p. R102-Article in journal (Refereed)
    Abstract [en]

    This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

  • 35. Wedrén, Sara
    et al.
    Lovmar, Lovisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Humphreys, Keith
    Magnusson, Cecilia
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fermer, Maria Lagerström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Persson, Ingemar
    Baron, John
    Weiderpass, Elisabete
    Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk: a case control study2004In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 6, no 4, p. R437-49Article in journal (Other academic)
    Abstract [en]

    INTRODUCTION: Oestrogen receptor alpha, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor alpha gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C --> T, 1557 cases and 1512 controls; c.454-351A --> G, 1556 cases and 1512 controls; c.729C --> T, 1562 cases and 1513 controls; c.975C --> G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A --> G or c.454-397C --> T and c.975C --> G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A --> G and c.975C --> G haplotype entailed an OR of 1.19 (95% CI 1.06-1.33) and two copies with an OR of 1.42 (95% CI 1.15-1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C --> T and c.975C --> G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women.

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