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Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer 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, Oncology . Linköping University, Faculty of Health Sciences.
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.

Place, publisher, year, edition, pages
2003. Vol. 63, 8742-8748 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13938OAI: oai:DiVA.org:liu-13938DiVA: diva2:22266
Available from: 2006-08-29 Created: 2006-08-29 Last updated: 2009-02-12
In thesis
1. Effects of sex steroids and tamoxifen on VEGF in the breast
Open this publication in new window or tab >>Effects of sex steroids and tamoxifen on VEGF in the breast
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
angiogenesis, breast cancer, estradiol, MCF-7, microdialysis, nude mice, progesterone, sVEGFR-1, VEGFR-2
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-7230 (URN)91-85497-91-6 (ISBN)
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

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Garvin, StinaDabrosin, Charlotta

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