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Effects of sex steroids and tamoxifen on VEGF in the breast
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on factors mediating angiogenesis, the development of new blood vessels, in normal and malignant breast tissue. In this thesis we have investigated the effects of estradiol, progesterone, and the nonsteroidal anti-estrogen tamoxifen on vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) in normal human breast tissue, endothelial cells, and breast cancer. We have applied the technique of microdialysis to provide in situ sampling of estradiol and VEGF in tumors and normal breast tissue of breast cancer patients in vivo. Furthermore, we present a novel method of culturing normal human breast tissue ex vivo.

Our results suggest a pro-angiogenic effect of estradiol and an anti-angiogenic effect of tamoxifen in the breast. Estradiol increased extracellular levels of VEGF in normal human breast tissue and breast cancer cells in vitro. In addition, estradiol decreased sVEGFR-1 in breast cancer cells and indirectly increased VEGFR-2 in endothelial cells. Compared to estradiol treatment alone, estradiol + tamoxifen increased sVEGFR-1 and decreased VEGF in breast cancer cells in vitro. Furthermore, estradiol + tamoxifen decreased tumor VEGF levels and tumor vasculature in human breast cancer xenografts in vivo. In breast cancer patients, a significant correlation was found between in vivo levels of estradiol and VEGF sampled by microdialysis in normal human breast tissue, suggesting that estradiol may be a potent regulator of VEGF in the breast in vivo. Tumor levels of VEGF were significantly higher than in normal breast tissue in vivo, supporting the role of VEGF in tumor angiogenesis. For studies of normal human breast, whole breast tissue may be cultured in vitro for up to one week with preserved morphology. Using this method, estradiol, and not progesterone, appears to be the main sex steroid regulator of extracellular VEGF in normal breast tissue. In conclusion, the data suggest that sex steroids and tamoxifen exert pro- and anti-angiogenic effects in normal breast tissue and breast cancer.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi , 2006.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 953
Keyword [en]
angiogenesis, breast cancer, estradiol, MCF-7, microdialysis, nude mice, progesterone, sVEGFR-1, VEGFR-2
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-7230ISBN: 91-85497-91-6 (print)OAI: oai:DiVA.org:liu-7230DiVA: diva2:22270
Public defence
2006-09-22, Berzeliussalen, Faculty of Health Sciences, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2006-08-29 Created: 2006-08-29 Last updated: 2009-08-22
List of papers
1. Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo
Open this publication in new window or tab >>Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo
2003 (English)In: Cancer research, ISSN 0008-5472, Vol. 63, 8742-8748 p.Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor (VEGF) is considered a key mediator of tumor angiogenesis, including neovascularization in human breast cancer. High tissue VEGF levels appear to correlate with poor prognosis and decreased overall survival in node-positive and node-negative breast cancer patients. Hormonal regulation of VEGF expression has been demonstrated, and some reports indicate that tamoxifen, a partial estrogen receptor agonist, increases VEGF mRNA in breast cancer cells. These results appear to contradict the efficacy of tamoxifen as an adjuvant for estrogen-dependent breast cancer, yet clinical data show that tamoxifen prevents metastasis and increases overall survival. In this study, we confirmed previous studies showing that intracellular levels of VEGF in vitro increased in response to tamoxifen to levels similar to those observed after estrogen treatment. To further study hormonal effects on the release of VEGF, we used microdialysis to sample the extracellular space, where VEGF is biologically active, in solid tumors in situ. We show for the first time that tamoxifen decreased extracellular VEGF in vivo in solid MCF-7 tumors in nude mice. These in vivo findings were confirmed in vitro where extracellular VEGF in the cell culture medium was decreased significantly by tamoxifen treatment. Furthermore, we illustrate that microdialysis is a viable method that may be applied in human breast tissue to detect soluble VEGF in situ released by the tumor.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13938 (URN)
Available from: 2006-08-29 Created: 2006-08-29 Last updated: 2009-02-12
2. Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells
Open this publication in new window or tab >>Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells
2005 (English)In: British journal of cancer, ISSN 0007-0920, Vol. 93, no 9, 1005-1010 p.Article in journal (Refereed) Published
Abstract [en]

Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

Keyword
breast cancer, flt-1, flk-1, KDR, MCF-7, nude mice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13939 (URN)10.1038/sj.bjc.6602824 (DOI)
Available from: 2006-08-29 Created: 2006-08-29
3. In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients
Open this publication in new window or tab >>In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients
2008 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 73, no 8Article in journal (Refereed) Published
Abstract [en]

Background: Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

Methods: Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

Results: We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

Conclusion: We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13940 (URN)10.1186/1471-2407-8-73 (DOI)
Available from: 2006-08-29 Created: 2006-08-29 Last updated: 2017-12-13
4. Estradiol increases VEGF in normal human breast studied by whole-tissue culture
Open this publication in new window or tab >>Estradiol increases VEGF in normal human breast studied by whole-tissue culture
Show others...
2006 (English)In: Cell Tissue Research, ISSN 0302-766X, Vol. 325, no 2, 245-251 p.Article in journal (Refereed) Published
Abstract [en]

Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on the normal breast, largely because of the lack of convenient models. We have developed a method of culturing normal breast tissue ex vivo. We have applied this method to investigate the effects of estradiol and progesterone on the key angiogenic mediator, vascular endothelial growth factor (VEGF), in the breast. Whole breast tissue was obtained from routine reduction mammoplasty. Tissue biopsies were cultured in vitro for 1–3 weeks, and the expression of luminal cytokeratin 18 was determined by immunohistochemistry. As an application, tissue biopsies were treated in vitro for 1 week with or without estradiol or estradiol and progesterone. Estrogen receptor, progesterone receptor, and Ki–67 were analyzed, and VEGF levels were examined by quantitative immunoassay and immunohistochemistry. Whole breast tissue was cultured ex vivo for 1 week with preserved morphology. Increased detachment of the luminal epithelium was observed after 2 weeks. Estradiol increased extracellular levels of VEGF in normal breast tissue biopsy medium. The addition of progesterone had neither stimulatory nor inhibitory effects on secreted VEGF. The method of whole breast tissue culturing thus provide a means by which to explore the biology of normal breast tissue. Our results suggest that estradiol exerts pro-angiogenic effects in normal breast by increasing levels of biologically active VEGF.

Keyword
Angiogenesis, Vascular endothelial growth factor, Cytokeratin 18, Extracellular expression, Luminal expression, Estradiol, Progesterone, Human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13941 (URN)10.1007/s00441-006-0159-7 (DOI)
Available from: 2006-08-29 Created: 2006-08-29

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