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Hormonal regulation of immune modulators in human breast tissue
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-117983DOI: 10.3384/diss.diva-117983ISBN: 978-91-7519-055-6 (print)OAI: oai:DiVA.org:liu-117983DiVA: diva2:812647
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
List of papers
1. Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
Open this publication in new window or tab >>Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86651 (URN)10.1210/jc.2012-2288 (DOI)000310710500002 ()
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
2. Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo
Open this publication in new window or tab >>Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo
2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 9, 3460-3467 p.Article in journal (Refereed) Published
Abstract [en]

Context: Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue. Objective: To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer. Setting and Design: Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated. Results: In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P less than .05) and positively correlated with leptin (r = 0.37; P less than .05) and leptin: adiponectin ratio (r = 0.38; P less than .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P less than 0.05) and decreased leptin (P less than .01) and the leptin: adiponectin ratio (P less than .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P less than .01) and adiponectin lower (P less than .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P less than .05). Conclusions: Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

Place, publisher, year, edition, pages
Endocrine Society, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111611 (URN)10.1210/jc.2014-1129 (DOI)000342341400088 ()24796929 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2012/454]; Swedish Research Council [2010-3458]; Research Funds of Linkoping University Hospital

Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-12-05
3. Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo
Open this publication in new window or tab >>Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo
2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Events in the microenvironment are important for carcinogenesis of the breast. Adipocytes, which produce adipokines with paracrine effects, are the most abundant cell type in breast tissue. Exposure to sex steroids affects the risk of breast cancer. It has previously been shown that estrogen regulates the extracellular levels of leptin, adiponectin, IL-1β, and VEGF in normal human breast tissue in vivo.

Objective: We aimed to determine if there were any relationships between leptin, adiponectin, IL-1β, and/or VEGF in normal human breast tissue in vivo and to elucidate the role of adipocytes in the regulation of these factors.

Design and methods: Microdialysis was used to sample proteins of normal human breast tissue and abdominal subcutaneous (s.c.) fat in situ in pre-and postmenopausal women. An in vitro co-culture model of breast cancer cells and primary mature human adipocytes was used.

Results: In vivo, in normal breast tissue, significant positive correlations between VEGF and leptin, and VEGF and leptin/adiponectin ratio were detected. No correlations were found in s.c. abdominal fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. In breast tissue, significant correlations between IL-1β and leptin and VEGF were revealed.

Conclusions: Our results suggest that VEGF regulates leptin in normal human breast tissue. Moreover, physical contact between adipocytes and breast cancer cells, induces phenotypic changes and enhances the effects of estradiol. These mechanisms may be involved in breast cancer progression.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117982 (URN)
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2015-05-19Bibliographically approved

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