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Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
2012 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 11, E2044-E2054 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

Place, publisher, year, edition, pages
Endocrine Society , 2012. Vol. 97, no 11, E2044-E2054 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-86651DOI: 10.1210/jc.2012-2288ISI: 000310710500002OAI: oai:DiVA.org:liu-86651DiVA: diva2:580093
Note

Funding Agencies|Swedish Cancer Society|2009/799|Swedish Research Council|2010-3458|Research Funds of Linkoping University Hospital||

Available from: 2012-12-20 Created: 2012-12-20 Last updated: 2017-12-06
In thesis
1. Hormonal regulation of immune modulators in human breast tissue
Open this publication in new window or tab >>Hormonal regulation of immune modulators in human breast tissue
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Breast cancer is the most common form of cancer and the second leading cause of malignancy-associated death in women worldwide. Estrogens are the main sex hormones in women. They are essential for the development and function of normal breast mammary glands; however, prolonged exposure to estrogens increases the risk of breast cancer development and progression. Approximately two-thirds of all breast cancer patients are positive for estrogen receptor (ER), but only 50% of those cases can benefit from antiestrogen therapy.

In this thesis we investigated the effects of estrogen, diet modification, and anti-estrogen drugs on several immune modulators in normal human breast tissue. We used the microdialysis technique to sample the immune modulators in situ in normal human breast tissue, in malignant breast tissue, and in tumor tissue from both the immune competent mice with murine breast cancer and immune deficient mice bearing human breast tumors. Furthermore, we also used ex vivo culture of normal breast tissue and in vitro cell culture of breast cancer cell lines. A combined cell culture (co-culture) of breast cancer cell lines, together with the primary mature adipocytes, was also used in this thesis.

In Paper I and Paper II, our results suggested that estrogen exerted both proinflammatory and pro-tumorigenic effects in normal human breast tissue. Estradiol increased extracellular interleukin-1β (IL-1β) and leptin levels and decreased IL-1Ra and adiponectin levels in normal human breast tissue. In contrast, tamoxifen decreased IL-1β and leptin levels and increased IL-1Ra and adiponectin levels, shifting the environment towards an antiinflammatory and antitumorigenic state. Diet modification with flaxseed for 30 days also increased IL-1Ra levels, creating an anti-inflammatory environment in normal breast tissue. In the breast cancer tissue, we found that extracellular IL-1β levels and leptin levels were significantly higher, whereas adiponectin levels were significantly lower, compared with normal adjacent breast tissue, which suggested a more proinflammatory state.

In the third paper, our in vivo investigation of normal breast tissue revealed significant correlations between vascular endothelial growth factor (VEGF) and leptin, IL-1β and leptin, and between VEGF and IL-1β. No correlations were found in the abdominal subcutaneous (s.c.) fat tissue. Our in vitro inhibition experiments suggested that VEGF was a potent regulator of leptin, but that leptin was not a potent regulator of VEGF. Co-culture per se altered the release of VEGF and leptin and enhanced the effects of estradiol, compared with monocultures of the included cell types.

In conclusion, the results presented in this thesis will increase the overall understanding of the role of estrogens in breast cancer, which may be useful in future treatment studies.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1461
National Category
Cancer and Oncology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117983 (URN)10.3384/diss.diva-117983 (DOI)978-91-7519-055-6 (ISBN)
Public defence
2015-06-05, Linden, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Cancer SocietySwedish Research CouncilLinköpings universitet
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2015-05-19Bibliographically approved

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Abrahamsson, AnnelieMorad, VivianDabrosin, Charlotta

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OncologyFaculty of Health SciencesDepartment of Clinical and Experimental MedicineDepartment of Oncology UHL
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Journal of Clinical Endocrinology and Metabolism
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