Rhim, J. S. Molecular and Genetic Mechanisms of Prostate Cancer.Prostate cancer is the most commonly diagnosed malignancy in American men and is the second leading cause of cancer death in males in the United States. Despite its high incidence, the molecular and genetic events involved in progression of prostate cancer remain poorly understood. In vitro models of human prostate epithelial (HPE) cells provide a practical approach to the analysis of the molecular and genetic mechanisms underlying prostate carcinogenesis. We reported the immortalization of normal adult HPE cells by transfection of the HPV-18 DNA and the subsequent conversion of such nontumorigenic but immortalized cells (HPV-18 C-1) into tumorigenic cells by the introduction of an activated Kras oncogene. Recently, we have demonstrated the malignant transformation of HPV-18 C-1 cells after multiple exposures to the chemical carcinogen N-nitroso-N-methylurea (NMU). Such transformants showed morphological alterations and anchorage-independent growth in soft agar and induced carcinomas when transplanted into nude mice. No TP53 or RAS mutations were observed. Stepwise chromosomal changes in the progression to tumorigenicity were observed. Loss of the p arms of chromosome 8 (p10>pter) and chromosome 10(p10>pter) and gain of the q arm of chromosome 8 (p10>ptr) (the most frequent cytogenetic changes observed directly in prostate cancer patients) were observed only in the tumor outgrowths. These findings provide the first evidence of malignant transformation of HPE cells exposed to a chemical carcinogen.