The importance of the stroma on epithelial transformation is not well characterized. Moreover, in the prostate gland the regulation of androgens mediated from the stroma in synergy with the epithelia is not well understood, particularly when combined with the effects of a well-known pathway, transforming growth factor-IS (TGF-?). It has been known that prostate homeostasis is maintained by androgens and TGF- ? to balance cell proliferation and apoptosis, yet the exact mechanisms and crosstalk that occur between these factors in the stroma and epithelia are unknown. We have previously developed mice with the TGF- ? type II receptor knocked out in mice under the fibroblast specific promoter (T?KO) to study the role of stromal fibroblasts in TGF- ? signaling. We found that the lack of TGF-? signaling in the prostate stroma causes the epithelia to form prostatic intraepithelial neoplasia lesions. More strikingly, the T?KO prostates do not regress upon androgen ablation. A paracrine factor involved in the stromal TGF- ? regulation of prostate androgen responsivity results in ?-catenin transcriptional activity in the prostate epithelial cells. We propose to study primary prostate mouse TGF- ? type II receptor floxed and F?KO cells in culture to examine the roles of TGF- ? signaling components on the androgen signaling pathway. To take our in vitro studies to in vivo mouse models we will use the tissue recombination technique recombining modified prostatic stromal cells with wild type or transformed epithelia. The host mice of the xenografted recombined tissues will be subjected to androgen, TGF- ? and or Wnt signaling regulation. The three aims of this proposal focus on different aspects of TGF- ? signaling in response to androgen ablation during prostate regression.
Aim 1 focuses on determining the TGF- ? signaling pathway components in the stroma during prostate regression.
Aim 2 focuses on determining which of these components are involved in prostate cancer regression.
Aim 3 focuses on the effects of stromal TGF- ? signaling in prostate regression on epithelial ? -catenin signaling. The multiple ways that the TGF- ?, androgen receptor, and Wnt pathways interact will undoubtedly prove to be interesting. The incidence of prostate cancer and benign prostate hyperplasia (BPH) continues to rise in the Western world. Surgery and androgen ablation therapy remains the major treatment for prostate cancer, however, within a year of treatment >80% of prostate cancer becomes androgen independent This proposal will increase the understanding on TGF- ? signaling in the stromal fibroblasts that affect the androgen responsiveness of the prostatic epithelia with the long term goal of contributing to the treatment of patients with androgen independent prostate cancer.
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