Prostate cancer is the second leading cause of cancer deaths in men. In 1992 the projected incidence of prostate cancer in the US is 122,000 with 32,000 deaths. The lack of progress in treatment and management of this disease is hampered by inadequate experimental animal models. The purpose of this project is to develop and establish an efficient and reproducible animal model system for inducing prostate carcinogenesis; analyze the molecular and cellular events following the development of prostate cancer and to identify agents that prevent and/or suppress prostate cancer incidence. We have induced prostate carcinogenesis by initiation with N- methyl-nitrosourea (NMU) and promotion with testosterone propionate (TP) in Lobund/Wistar rats of varying age ranging from 2-4 months old. After 11-12 months post NMU/TP treatment, tumor incidence in the prostate and other accessory sex organs was approximately 70%. Molecular changes in the tumor show K-ras mutation of codon 12 (60%) and elevation of testosterone repressed message-2 (TRPM-2) gene. We have succeeded in growing primary cultures of rat prostate epithelium in rats treated with NMU/TP for 7 months. We have immortalized 2 cell lines that are responsive to androgens and exogenous growth factors. Using 3 month old rats, we have shown increased levels of TGF-Beta 1 and Beta 3 message and protein at 3-6 days following castration. This effect was reversed by treatment with TP. In collaboration with Dr. Morris Pollard, Lobund Laboratory, we have demonstrated for the first time decreased incidence of prostate cancer in MNU/TP treated animals fed with N-(4-Hydroxyphenyl)retinamide.
