Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
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.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The prognosis of patients diagnosed with breast cancer has been considerably improved in the latest 25 years, as a result of continuous development of diagnostics and treatment regimens. Though, tumour diseases, for woman mainly lung cancer and breast cancer, still constitute of the most common causes of death in developed countries, following heart diseases. A future utopia is to develop more individualised therapy strategies, to further increase breast cancer survival, but also to decrease  the risk of severe side-effects of unnecessary treatments.

Normal mammary gland development is regulated by a complex interplay between growth factors and hormones, mainly oestrogen and progesterone, in different cell types. Breast cancer origin and progression is assumed to result from an imbalance in this interplay, leading to the so called “Hallmarks of cancer”, including unlimited cellular proliferation. A central hub in the regulation of proliferation is the intracellular mTOR signalling pathway. Antioestrogen therapy is widely used in breast cancer clinics, however resistance towards this treatment is a remaining problem, and overactivation of mTOR may be one reason behind. A new treatment regimen constituting a combination of mTOR inhibitors with endocrine therapy was recently clinically approved for advanced breast cancers. Although significant benefit for this combination treatment is evident for some patients, counteracting feedback mechanisms are assumed to diminish the effects.

The work presented in this thesis focuses on the genes S6K1, S6K2 and 4EBP1 which are main effectors of the intracellular mTOR signalling pathway and thereby secondary targets of the mTOR inhibitors. Our results suggests that the gene amplification status, expression levels of the corresponding mRNA and protein of S6K1, S6K2 and 4EBP1 as well as their cellular localisation may be used to predict breast cancer outcome and the benefit from antioestrogen treatments. These factors are indicated to play separate roles in different subtypes of breast cancer, and specific targeting of S6K1 and S6K2 may be valuable in different tumour subtypes, and in comparison to present day’s mTOR inhibitors, further promote individualised therapies, and thereby increase breast cancer survival.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 127 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1388
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-104180DOI: 10.3384/diss.diva-104180ISBN: 978-91-7519-432-5 (print)OAI: oai:DiVA.org:liu-104180DiVA: diva2:695104
Public defence
2014-03-07, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-02-10 Created: 2014-02-10 Last updated: 2017-01-11Bibliographically approved
List of papers
1. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
Open this publication in new window or tab >>Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
Show others...
2011 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, no 3, 713-723 p.Article in journal (Refereed) Published
Abstract [en]

The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
Keyword
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69784 (URN)10.1007/s10549-010-1058-x (DOI)000292557100013 ()
Note
The original publication is available at www.springerlink.com: Gizeh Perez-Tenorio, Elin Karlsson, Marie Ahnström, Birgit Olsson, Birgitta Holmlund, Bo Nordenskjöld, Tommy Fornander, Lambert Skoog and Olle Stål, Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, 2011, Breast Cancer Research and Treatment, (128), 3, 713-723. http://dx.doi.org/10.1007/s10549-010-1058-x Copyright: Springer Science Business Media http://www.springerlink.com/Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
2. High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP1
Open this publication in new window or tab >>High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP1
Show others...
2011 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, no 10, 775-787 p.Article in journal (Refereed) Published
Abstract [en]

The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [ RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70514 (URN)10.1002/gcc.20900 (DOI)000294177300003 ()
Note

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||

Available from: 2011-09-12 Created: 2011-09-12 Last updated: 2017-12-08
3. 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.
Open this publication in new window or tab >>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.
Show others...
2013 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 5, R96- p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keyword
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-104178 (URN)10.1186/bcr3557 (DOI)000329763800024 ()24131622 (PubMedID)
Available from: 2014-02-10 Created: 2014-02-10 Last updated: 2017-12-06Bibliographically approved
4. Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis
Open this publication in new window or tab >>Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis
Show others...
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, e0145013- p.Article in journal (Refereed) Published
Abstract [en]

Background

The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.

Materials and methods

Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.

Results

Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

Place, publisher, year, edition, pages
Public Library Science, 2015
National Category
Clinical Medicine Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-124494 (URN)10.1371/journal.pone.0145013 (DOI)000367092600042 ()26698305 (PubMedID)
Note

At the time for thesis presentation publication was in status: Manuscript

Funding Agencies|Swedish Research Council [2012-5136, 2007-3475]; Swedish Cancer Foundation; LiU Cancer; LiU Cancer Foundation

Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30Bibliographically approved

Open Access in DiVA

Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer(9708 kB)781 downloads
File information
File name FULLTEXT01.pdfFile size 9708 kBChecksum SHA-512
f38f9443d30f392bea93567ec588a25d7305c36a95e3d85c94b5304b6b1252da1eb7d414ae78fa40cd89340c3d690ee8e06fa1fdc7b1c11e8d5d0c8dbcfc83f4
Type fulltextMimetype application/pdf
omslag(7524 kB)34 downloads
File information
File name COVER01.pdfFile size 7524 kBChecksum SHA-512
25435b5887602aeb833555bc06ba14add606331b654e246c33dce0d64dca0d1a3430b72990c596b6a2ac46083f763cb8e3032782c98fb97881fa2e9238ac8efd
Type coverMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Karlsson, Elin
By organisation
Division of Clinical SciencesFaculty of Health SciencesDepartment of Oncology
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 781 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 863 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf