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Dalton Cardiovascular Research Center and Biomedical Sciences, University of Missouri, Columbia, Missouri 65211
Address all correspondence and requests for reprints to: Dr. Salman M. Hyder, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, Missouri 65211. E-mail: hyders{at}missouri.edu.
Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of progestin-induced VEGF by the antiprogestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to progestins, suggests that these effects are mediated by amplification of the progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.
This article has been cited by other articles:
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  Y. Liang, C. Besch-Williford, R. A. Brekken, and S. M. Hyder Progestin-Dependent Progression of Human Breast Tumor Xenografts: A Novel Model for Evaluating Antitumor Therapeutics Cancer Res., October 15, 2007; 67(20): 9929 - 9936. [Abstract] [Full Text] [PDF]
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 A. Y. Ting, B. F. Kimler, C. J. Fabian, and B. K. Petroff Characterization of a preclinical model of simultaneous breast and ovarian cancer progression Carcinogenesis, January 1, 2007; 28(1): 130 - 135. [Abstract] [Full Text] [PDF]
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 S M Hyder Sex-steroid regulation of vascular endothelial growth factor in breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 667 - 687. [Abstract] [Full Text] [PDF]
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Y. Liang, R. A Brekken, and S. M Hyder Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr. Relat. Cancer, September 1, 2006; 13(3): 905 - 919. [Abstract] [Full Text] [PDF]
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 I. Benakanakere, C. Besch-Williford, J. Schnell, S. Brandt, M. R. Ellersieck, A. Molinolo, and S. M. Hyder Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats. Clin. Cancer Res., July 1, 2006; 12(13): 4062 - 4071. [Abstract] [Full Text] [PDF]
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