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Correlation between vascular endothelial growth factor and leptin in normal human breast tissue in vivo
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
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.
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.

Place, publisher, year, edition, pages
2015.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-117982OAI: oai:DiVA.org:liu-117982DiVA: diva2:812639
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2015-05-19Bibliographically approved
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 (print) (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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Morad, VivianAbrahamsson, AnnelieKjölhede, PrebenDabrosin, Charlotta
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Division of Clinical SciencesFaculty of Health SciencesDepartment of Gynaecology and Obstetrics in LinköpingDepartment of Oncology
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