Epidemiologic and experimental studies suggest that oral contraceptives (OCP) as well as the retinoid fenretinide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms underlying the chemopreventive activity of these agents are not well understood. Conventional and molecular epidemiology has not correlated risk of ovarian cancer with frequency of ovulation, but the decreased risk from OCP is not directly proportional to the fraction of cycles suppressed, suggesting that other mechanisms might also contribute to chemoprevention. Retinoids increase the production of TGFbeta by stromal cells in other tissues; further, we have demonstrated that retinoids and TGFbeta induce synergistic death in ovarian cancer cell lines as well as in freshly isolated tumor cells. 4-HPR decreased the incidence of ovarian cancer in a large Italian breast chemoprevention trial. Women with BRCA1 or BRCA2 mutations and a family history of ovarian cancer have a much higher risk of developing ovarian cancer than the general low risk population. Studies have shown that prior OCP use reduces the risk of ovarian cancer in both low and high risk women by about 50%. A recent study in primates indicates that treatment with oral contraceptives or progestins can increase apoptosis in ovarian surface epithelial cells, thus perhaps lessening the chance that a genetic alteration will occur which could lead to cancer. TGFbeta is thought both to suppress the proliferation of ovarian surface epithelial cells and to induce apoptosis in transformed cells, thus providing a primitive surveillance mechanism for eliminating emerging clones of malignant cells. We hypothesize that both OCP and retinoids increase the production of TGFbeta from ovarian stromal cells and induce apoptosis in epithelial cells. Preliminary studies suggest that fiber-optic spectroscopy may be able to identify cancerous and precancerous changes on the ovarian surface and subsurface, and thus may provide a unique marker for assessment in chemoprevention trials. We will explore the hypotheses that: 1) 4-HPR and OCP induce apoptosis in ovarian surface epithelial cells. 2) TGFbeta produced by ovarian stromal cells contributes to apoptosis and differentially affects normal and transformed cells. 3) OCP and 4-HPR may affect low and high risk ovarian epithelium differently; these differences will be detectable through variations in intermediary markers. 4) Spectroscopy provides a unique intermediary marker to detect early dysplastic or pre-malignant changes in ovarian epithelial cells as well as reliably identifying both early proliferative changes and apoptotic changes that may change with chemoprevention. To investigate these hypotheses, we propose two randomized placebo- controlled chemoprevention trials in women at low risk (no history, no known mutations) or at high risk (BRCA1 or BRCA2 mutations, or family history), optical spectroscopy. These pilot studies should elucidate mechanisms of chemoprevention in ovarian cancer, identify relevant intermediate biomarkers, and help in development of definitive chemoprevention trials for high risk women.
