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Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 746Article in journal (Refereed) Published
Abstract [en]

Mammographic breast density is a strong independent risk factor for breast cancer (BC), but the molecular mechanisms behind this risk is yet undetermined and prevention strategies for these women are lacking. The anti-estrogen tamoxifen may reduce the risk of BC but this treatment is associated with severe side effects. Thus, other means for BC prevention, such as diet interventions, need to be developed. Osteopontin (OPN) is a major mediator of inflammation which is key in carcinogenesis. OPN may be cleaved by proteases in the tissue and cleaved OPN may in turn induce an inflammatory cascade in the extracellular microenvironment. We aimed to determine if extracellular OPN was altered in BC and in normal breast tissue with different densities and if tamoxifen or a diet of flaxseed could modify OPN levels. The study comprised 103 women; 13 diagnosed with BC, 42 healthy post-menopausal women with different breast densities at their mammography screen, and 34 post-menopausal women who added 25 g of ground flaxseed/day or were treated with tamoxifen 20 mg/day and were investigated before and after 6 weeks of exposure. Additionally, 10 premenopausal women who added flaxseed for one menstrual cycle and four who were investigated in two unexposed consecutive luteal phases of the menstrual cycle. Microdialysis was used to sample extracellular proteins in vivo in breast tissue and proteins were quantified using a multiplex proximity extension assay. We found that, similar to BC, extracellular in vivo OPN levels were significantly increased in dense breast tissue. Additionally, significant correlations were found between OPN and chemokine (C-X-C motif) ligand (CXCL)-1, -8, -9, -10, and - 11, interleukin-6, vascular endothelial growth factor, matrix metalloproteinase (MMP)-1, - 2, -3, 7, and -12 and urokinase-type plasminogen activator whereas no correlations were found with MMP-9, chemokine (C-C motif) ligand (CCL)-2, and -5. Estradiol did not affect OPN levels in breast tissue. None of the interventions altered OPN levels. The pro-tumorigenic protein OPN may indeed be a molecular target for BC prevention in women with increased breast density but other means than tamoxifen or flaxseed i.e., more potent anti-inflammatory approaches, need to be evaluated for this purpose.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 9, article id 746
Keywords [en]
inflammation; microdialysis; tamoxifen; flaxseed; enterolactone
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-160039DOI: 10.3389/fonc.2019.00746ISI: 000481427600001PubMedID: 31475105OAI: oai:DiVA.org:liu-160039DiVA, id: diva2:1349072
Note

Funding Agencies|Swedish Cancer Society [2018/464]; Swedish Research Council [2018-02584]; LiU-Cancer; ALF of Linkoping University Hospital

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-11-26
In thesis
1. The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer
Open this publication in new window or tab >>The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Breast cancer is the most common cancer among women worldwide today. Nearly 9000 women are diagnosed with breast cancer in Sweden yearly and despite advantages in diagnostics and treatments approximately 1400 women still die from their disease every year. Breast cancer has a diverse etiology and hormonal factors and life-style factors contribute to an increased breast cancer risk. High mammographic density is also considered a risk factor but the underlying mechanisms are not fully understood. Inflammation is associated with poor survival in several malignancies and is considered a hallmark of cancer. There is evidence indicating that increased inflammation is associated with dense breast tissue and may contribute to an increased risk of breast cancer in these patients.

There is an urgent need to find risk reduction strategies in breast cancer prevention. Several studies have shown that antiestrogens significantly reduce breast cancer incidence in women with high risk of developing breast cancer and can be used for chemoprevention. These drugs may have potentially severe side effects and other strategies are needed. Dietary interventions may influence breast cancer risk without any major side effects. Studies indicate that dietary phytoestrogens may reduce breast cancer risk. The most common phytoestrogens in Western populations are lignans, mainly found in flaxseed, but results from several studies with lignans for breast cancer prevention have been inconsistent.

In this thesis we investigated the effects of tamoxifen and flaxseed on inflammatory mediators in normal breast tissue and in breast cancer. We used the microdialysis technique to sample proteins from the extracellular space in vivo. This technique gives us the opportunity to study proteins in their bioactive compartment in situ and to study changes in protein levels at different time points without affecting the tissue of interest. We also used experimental models and cell cultures to study tumor growth of human breast cancer xenografts, cancer cell proliferation and angiogenesis.

In paper I, we investigated whether tamoxifen, flaxseed, enterolactone or genestein reduced growth of human breast cancer xenografts and their association with pro-inflammatory cytokine interleukin 1β (IL-1β) and its antagonist interleukin 1 receptor antagonist (IL-1Ra). In paper II, we investigated whether tamoxifen and flaxseed exerted similar effects on inflammatory mediators in normal breast tissue in vivo. In paper III, we investigated whether osteopontin (OPN), a pro-inflammatory cytokine, was associated with dense breast tissue and breast cancer and if tamoxifen and flaxseed could alter OPN levels in normal breast tissue in vivo. We also investigated the correlation between OPN and inflammatory mediators in normal breast tissue and in breast cancer in vivo.

In conclusion, we showed that tamoxifen and flaxseed affected breast cancer growth in an experimental model and may exert an anti-inflammatory effect in breast cancer and normal breast tissue by increasing the IL-1Ra/IL-1β ratio in vivo. We showed that dense breast tissue and breast cancer were associated with increased levels of OPN. Circulating estrogen did not correlate to OPN and tamoxifen and flaxseed did not affect OPN levels suggesting an estrogen independent regulation of OPN in vivo. These finding contributes to our understanding of how tamoxifen and flaxseed affects inflammation and the role of inflammation in the pathogenesis of breast cancer.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 63
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1714
Keywords
breast cancer, inflammation, chemoprevention, tamoxifen, phytoestrogens, flaxseed, enterolactone, interleukins, osteopontin, chemokines, matrix metalloproteases, microdialysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-161062 (URN)10.3384/diss.diva-161062 (DOI)9789179299637 (ISBN)
Public defence
2019-11-29, Eken, Hus 421, Campus US, Linköping, 13:00 (Swedish)
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Supervisors
Available from: 2019-10-21 Created: 2019-10-19 Last updated: 2019-11-01Bibliographically approved

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