Curcumin inhibits secretion of progestin-induced vascular endothelial growth factor from human breast cancer cells. Free

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Postmenopausal women receiving estrogens for hormone replacement therapy (HRT) are also given a progestin (usually medroxyprogesterone acetate [MPA]) to prevent endometrial cancer if they have an intact uterus. Unfortunately, recent studies show that women receiving the combined treatment have a greater risk of breast cancer than women receiving estrogens alone or placebo. We recently showed that progestins increase the expression of VEGF, a potent angiogenic factor, in human breast cancer cells that express ER/PR as well as mutant p53 protein. Elevated levels of VEGF promote angiogenesis, or formation of new blood vessels in breast tissue, and lead to tumor progression. Clearly, safer additives are needed to counteract the undesirable side-effects of the progestins component of combined HRT. Curcumin (a turmeric root derivative) is an Indian spice that has recently gained popularity as an anti-angiogenic and cancer preventive agent; however, whether curcumin can treat or prevent progestin-accelerated breast cancer is unknown. In this study we treated T47-D human breast cancer cells with 10^-8M MPA and/or curcumin (0.001-10μM) for 16-18 hours and measured secreted VEGF protein levels using VEGF ELISA. Our findings show that curcumin dose-dependently inhibits MPA-induced VEGF secretion in T47-D cells. Since VEGF promotes angiogenesis, our results strongly suggest that curcumin may be able to inhibit progestin-dependent angiogenesis and hence tumor progression. To determine whether curcumin can inhibit progestin-dependent breast cancer growth, we utilized our recently established progestin-accelerated breast cancer model in which MPA accelerates 7, 12-dimethylbenz[a]anthracene (DMBA)-initiated mammary tumors by increasing angiogenesis in Sprague-Dawley rats. Using intact, virgin, female Sprague-Dawley rats, we administered DMBA (20mg/rat) via gavage. Three days prior to subcutaneous implantation of MPA (25mg, 60 day time release, placed on day 28 following DMBA treatment), or placebo pellets, we began administering 200mg/kg/day curcumin daily by a single intraperitoneal (i.p.) injection for 1 week, followed by injections of curcumin every second day for an additional two weeks. Preliminary data shows that curcumin increases the latency period of MPA-driven tumorigenesis. We suggest therefore that, subject to further studies, curcumin may show significant promise as an anti-angiogenesis/anti-tumor agent which could be administered to humans in concert with combined HRT to ameliorate the undesirable side-effects of the progestin component and thereby reduce or prevent progestin-accelerated tumors. This research was supported by NIH grant CA-86916; Phi Zeta Award from University of Missouri; and by PDF0600723 from Susan G Komen Breast Cancer Foundation. SMH is Zalk Missouri Professor of Tumor Angiogenesis.