Prostate cancer is the second leading cause of cancer death in men. In 1992 the incidence of prostate cancer in the U.S. was 122,000 with 32,000 deaths. The lack of progress in prevention of this disease is hampered by inadequate experimental animal models. The purpose of this project is to develop a reproducible animal model system for studying prostate carcinogenesis, and identify agents that prevent and/or suppress prostate cancer incidence and their mechanisms of action. We have induced prostate carcinogenesis by initiation with N-methyl-nitrosourea (NMU) and promotion with testosterone propionate (TP) in 3-month old Lobund-Wistar rats. After 11-12 months post NMU/TP treatment, tumor incidence in the prostate and other accessory sex organs was approximately 70%. Treatment with tamoxifen, 4-HPR and deltanoid (Ro 24-5531) decreased tumor incidence in the prostate-seminal vesicle complex. We have developed tumorigenic (NRP-154) and non-tumorigenic (NRP-152) cell lines from rat dorsal-lateral prostate. NRP-152 cells are highly responsive to androgens, several other steroid hormones and many growth factors. Inhibition of growth by retinoic acid is mediated by induction of TGF-beta. Conversely, testosterone and dihydrotestosterone down-regulate expression of TGF-beta in NRP-152 cells. Finally, we have also shown that TGF-beta1 induces apoptosis of NRP-152 and NRP-154 cells. Thus, these newly developed cell lines are an important tool for mechanistic studies of carcinogenesis and chemoprevention in this tissue.
