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Submitted on January 25, 2005
Accepted on April 11, 2005
Dalton Cardiovascular Research Center and Biomedical Sciences, University of Missouri, Columbia, MO 65211
* To whom correspondence should be addressed. 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 synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor (PR)-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce proliferation of endothelial cells in a paracrine manner and induce 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 the 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 anti-progestin RU-486 eliminated VEGF induced proliferative effects. The ability of VEGF to increase 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 release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and the VEGFR-2 on both the 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 PR modulators that prevent the release of angiogenic growth factors from the breast cancer cells.
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