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Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells
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.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
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.

Place, publisher, year, edition, pages
2005. Vol. 93, no 9, 1005-1010 p.
Keyword [en]
breast cancer, flt-1, flk-1, KDR, MCF-7, nude mice
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13939DOI: 10.1038/sj.bjc.6602824OAI: oai:DiVA.org:liu-13939DiVA: diva2:22267
Available from: 2006-08-29 Created: 2006-08-29
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, StinaNilsson, Ulrika W.Dabrosin, Charlotta

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