Although prostate cancer is a major cause of cancer-related deaths in men over forty years of age, its etiology remains unknown. Previously, we have shown that carcinogens and testosterone induce hyperplasia and anaplasia in prostate explants and retinoids reverse these lesions. Frequently, the lesions induced by carcinogens are characterized as preneoplastic although the neoplastic nature of the carcinogen-treated explants or cell lines derived from such explants has not been demonstrated. The major objectives of this proposal are: first, to develop an in vitro model to demonstrate neoplastic transformation in carcinogen-treated prostate explants; second, to examine the prophylactic effects of all-trans-retinoic acid in cell lines derived from prostate explants exhibiting lesions. The neoplastic nature of prostate lesions will be examined in cell lines derived from the carcinogen-treated explants. The transformed phenotypes will be quantitated using three end points: (a) cloning efficiency, (b) anchorage-independent growth, and (c) tumorigenicity in syngeneic or nude hosts. Since the characteristics of carcinogen- and testosterone-induced lesions in prostate explants are different, our third major objective is to define the genesis of the lesions by elucidating for reserve and secretory cells, cytokinetic (cell cycle growth fraction, cell turnover time, and cell loss) and ultrastructural alterations associated with the induction and progression of prostate lesions caused by carcinogens and androgens. Retinoids have prophylactic and therapeutic effects against many epithelial tumors, and since they also inhibit and reverse lesions induced by carcinogens and testosterone in the mouse prostate organ culture, the fourth major objective is to elucidate cytokinetic and ultrastructural alterations associated with inhibition and reversal of prostate lesions by retinoids. Since sensitivities of dorsal and ventral prostate gland to carcinogens and testosterone may vary, both glands will be examined with respect to these alterations.