) Background: Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and fenretinide, N-(4hydroxypheny1) retinamide (4-HPR), may reduce the risk of developing epithelial ovarian cancer, but mechanisms underlying the chemopreventive activity of these agents remain unknown. Studies in primates and with human ovarian explants suggest that 4-HPR and progestins can induce TGF beta in stromal cells and apoptosis in the ovarian surface epithelium (OSE). Either 4-HPR or a combination of progestin and TGF beta can induce apoptosis in immortalized OSE (IOSE). 4-HPR can induce apoptosis in isolated normal OSE and this is enhanced with TGF beta. 4-HPR induces apoptosis in different tumor cell lines by generating reactive oxygen species or by binding to retinoic acid receptors. TGF beta and retinoids induce apoptosis by downregulating anti-apoptotic proteins. Hypotheses and Specific Aims: Based on these data, we will test the hypothesis that a combination of OCP and 4-HPR will induce apoptosis in a greater fraction of OSE than either agent alone, related in part to the production of TGF beta by ovarian stromal cells. We propose that 4-HPR induces apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptotoic proteins. TGF beta can augment apoptosis produced by 4-HPR or by progestin. In this portion of the SPORE we will (1) explore mechanisms underlying the chemopreventive activity of OCP and 4-HPR in OSE from women at normal and increased risk of ovarian cancer, (2) seek novel bio-markers for the impact of TGF beta on apoptosis induced by progestin, and (3) conduct a series of clinical trials to test the impact of OCP and an optimal dose of 4-HPR, individually and in combination, on induction of TGF beta in the stroma and apoptosis in the OSE of women at normal and increased risk of ovarian cancer. Significance: These studies may provide a rationale for the combined use of two promising agents for preventing ovarian cancer and elucidate mechanisms of their action.
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