Role of the TGFBeta1 in the Prevention of Prostate Cancer
Abstract
Our preliminary data showed that antiandrogen (toremifene) and antiestrogen (flutamide) prevented cancer in the TRAMP transgenic model. We hypothesized that these agents inhibit prostate carcinogenesis through stimulation of TGFBeta production. This hypothesis was tested through two specific aims: 1) whether the chemopreventive effects of antiandrogens, antiestrogens and retinoic acid are mediated by TGFBeta, 2) whether prostate cancer may be prevented in the TRAMP model at the genetic level by crossbreeding with transgenic mice engineered to overexpress TGFB. The retinoid MDI301 was ineffective. Both flutamide and toremifene delayed onset of prostate cancer but by different mechanisms: flutamide inhibited but toremifene did not affect large T-antigen expression. Toremifene treatment elevated total and free testosterone levels but did not affect androgen receptor levels suggesting its action through non-androgenic pathway. We explored if toremifene chemopreventive activity involved TGFBeta pathway. Toremifene had no influence on TGFBetal and TGFBeta2 but elevated TGFBeta3. Since both TGFBetaRI and RII were absent in the TRAMP prostate and toremifene failed to restore their expression, it appears that toremifene action is independent of the TGFB pathway. The results of crossbreeding experiments showed that overexpressed TGFBeta in prostate or seminal vesicles delayed tumor development in TRAMP mice through autocrine and paracrine pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2002
- Accession Number
- ADB283529
Entities
People
- Mitchell Steiner
Organizations
- University of Tennessee