The importance of stromal-epithelial interactions in prostate gland development and tumorigenesis is well established. These interactions likely involve autocrine and paracrine action of multiple growth factors, including members of the transforming growth factor-beta (TGFbeta) family. There is a coincident rise in TGFbeta expression following androgen ablation associated with regression of normal prostates. We used conditional knockout mice having a specific loss of the TGFbeta receptor type II in fibroblasts (FbetaKO) and prostate epithelia (EbetaKO) to identify the cellular component responding to TGFbeta signaling during prostate regression. The FbetaKO mice do not exhibit prostate regression upon androgen ablation. In contrast, EbetaKO mice displayed similar androgen responsiveness compared to non-transgenic mice. Interestingly, the TGFbeta signaling pathway, known to regulate androgen receptor action when activated in epithelial cells, can indirectly inhibit epithelial proliferation when activated in adjacent stromal fibroblasts. These findings are specifically relevant to our understanding of current androgen signaling antagonist treatments used in treating patients with malignant prostate cancer, benign prostate hyperplasia, and as a chemoprevention of prostate cancer in clinical trials. The central hypothesis of this application is that stromal TGFbeta signaling plays an important role in stromal-epithelial interactions responsible for prostate androgen responsiveness. The goal of this project is to specifically identify the TGFbeta-mediated signals in the stroma that mediate prostate androgen responsiveness. The EbetaKO and FbetaKO transgenic mouse models, tissue recombination xenograft models, and cell co-culture models will be used to determine the mechanism of TGFbeta regulation in prostate regression through the following specific aims: 1. Define the role of prostatic TGFbeta signaling as a result of androgen ablation. 2. Identify stromal TGFbeta downstream signaling pathway components for involvement in prostate regression. 3. Define TGFbeta signaling pathway components involved in prostate cancer regression.
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