PROGESTIN REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN HUMAN BREAST-CANCER CELLS

Vascular endothelial growth factor (VEGF) is a potent angiogenic facto r associated with the degree of vascularity, progression, and metastas is of breast cancer, and cases of this disease with increased vascular density have a poor prognosis, We show that in T47-D human breast can cer cells, progesterone induces a dose-dependent increase of 3-4-fold in media VEGF levels, with a maximum response occurring at a concentra tion of 10 nM. This effect is blocked by the antiprogestin RU 486. In addition to progesterone, a number of synthetic progestins used in ora l contraceptives (e.g., norethindrone, norgestrel, and norethynodrel), hormone replacement therapy (medroxyprogesterone acetate), and high-d ose progestin treatment of breast cancer (megestrol acetate) also incr ease VEGF in the media of cultured T47-D cells. This effect is hormone specific and is not produced by estrogens, androgens, or glucocortico ids. Collectively, these observations suggest that the increase in VEG F caused by progestins is mediated by progesterone receptors present i n T47-D cells. The induction of VEGF by progestins is also cell type s pecific and does not occur in human breast cancer cell lines MCF-7, ZR -75, or MDA-MB-231, nor in Ishikawa cells derived from a human endomet rial carcinoma. This is the first report that progestins regulate VEGF expression in human breast cancer cells and raises the possibility th at increased angiogenesis in response to endogenous progesterone or it s therapeutically used analogues may play a role in cell growth or met astasis in a subset of human breast tumors.