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The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer
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)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 [en]
breast cancer, inflammation, chemoprevention, tamoxifen, phytoestrogens, flaxseed, enterolactone, interleukins, osteopontin, chemokines, matrix metalloproteases, microdialysis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-161062DOI: 10.3384/diss.diva-161062ISBN: 9789179299637 (print)OAI: oai:DiVA.org:liu-161062DiVA, id: diva2:1362406
Public defence
2019-11-29, Eken, Hus 421, Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-10-21 Created: 2019-10-19 Last updated: 2019-12-12Bibliographically approved
List of papers
1. Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer
Open this publication in new window or tab >>Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer
2011 (English)In: CANCER RESEARCH, ISSN 0008-5472, Vol. 71, no 1, p. 51-60Article in journal (Refereed) Published
Abstract [en]

The proinflammatory cytokines IL-1 alpha and IL-1 beta promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1 beta derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell-released IL-1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65567 (URN)10.1158/0008-5472.CAN-10-2289 (DOI)000285826800007 ()
Available from: 2011-02-11 Created: 2011-02-11 Last updated: 2019-11-01
2. Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women
Open this publication in new window or tab >>Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women
2019 (English)In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 73, no 9, p. 1250-1259Article in journal (Refereed) Published
Abstract [en]

Background Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression. Subjects A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures. Results Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1 beta ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1 beta, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3. Conclusions We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-160614 (URN)10.1038/s41430-019-0396-y (DOI)000484395100006 ()30692654 (PubMedID)
Note

Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [2015/309]; Swedish Research CouncilSwedish Research Council [20132457]; ALF of Linkoping University Hospital

Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-11-01
3. Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
Open this publication in new window or tab >>Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ
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
Keywords
inflammation; microdialysis; tamoxifen; flaxseed; enterolactone
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-160039 (URN)10.3389/fonc.2019.00746 (DOI)000481427600001 ()31475105 (PubMedID)
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

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