Role of the TGF-B-1 in the Prevention of Prostate Cancer

Abstract : Our preliminary data showed that antiestrogen (toremifene) and antiandrogen (flutamide) prevented cancer in the TRAMP transgenic mouse model. Moreover, retinoids have been reported to prevent prostate cancer. However, the mechanism of prostate cancer prevention by these agents is unclear. We hypothesized that these agents inhibit prostate carcinogenesis through stimulation of TGF beta production. This hypothesis is being tested in TRAMP transgenic mice through two specific aims: 1) whether the chemopreventive biologic effects of antiandrogens, antiestrogens, and retinoic acid are mediated by TGF beta 1 in the TRAMP model, 2) whether prostate cancer may be prevented in the TRAMP model at the genetic level by crossbreeding with transgenic mice engineered to overexpress TGF beta 1 in the prostate. By detailed wholemount and histologic analyses flutamide, and toremifene were able to delay onset of prostate cancer. The mechanism of this suppression of prostate cancer may be different for the two agents: flutamide inhibited large T antigen expression, whereas toremifene had no affect on large T antigen expression. The retinoic acid derivative did not inhibit the onset of prostate cancer and as such did not demonstrate chemopreventive activity. Transgenic mice engineered to overexpress prostatic TGF beta 1 had smaller prostates.