Like most other cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. During the metastatic phase of this illness tumor cells often lose cell-cell contact and possess a more aggressive growth phenotype. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important in the growth and progression of prostate cancer. Recent studies have shown that the androgen-signaling pathway is regulated by multiple proteins, at different levels, and through distinct mechanisms. Dys-regulation of the androgen-signaling pathway may directly contribute to the development and progression of prostate cancer. The Wnt signaling pathway and its key component, ?-catenin, play a critical role in embryogenesis and tumorigenesis. Accumulated evidence has demonstrated a significant role for the Wnt pathway in the development and progression of prostate cancer. The discovery of an interaction between ?-catenin and AR suggests an important mechanism of the crosstalk between Wnt and androgen signaling pathways in prostate cancer cells. Since mutations in Adenomatous polyposis coli (APC), ?-catenin, and other components of the destruction complex are rare in prostate cancer cells, other regulatory mechanisms appear to play dominant roles in the activation of ?-catenin, such as abnormal activation of Wnt ligands, receptors, and other coregulators, loss and reduction of E-cadherin, or dys-regulation of other co-regulators and modulators of ?- catenin. In the recent years, we identified a promoting role of Wnt3A in the AR-mediated transcription and in the growth and survival of prostate cancer cells. We also demonstrated the effect of PTEN, E-cadherin, and the IGF1 growth factor on regulating cytoplasmic and nuclear level of ?-catenin. Based on these lines of evidence, we hypothesize that Wnt/?-catenin mediated signaling pathways play a critical role in prostate cells and that the dysregulation of these pathways through different regulators and modulators are important in prostate cancer development and progression. In this revised competing renewal, we propose a series of experiments to further address the roles and regulations of Wnt/?-catenin mediated signaling pathways in prostate tumorigenesis. Ultimately, we wish to identify the regulatory mechanism(s) of Wnt3A in androgenindependent prostate cancer cell growth (Aim 1), determine the biological roles of PTEN and its interaction with ?-catenin (Aim 2), and elucidate the physiological significance and molecular mechanism of E-cadherin in AR-mediated cell growth and survival (Aim 3). In addition, we also expect to generate several useful animal models and key reagents to study the pathogenesis of prostate cancer. We feel that the data generated by the successful completion of the Specific Aims will help us to further understand the roles of Wnt/?-catenin and its interaction with other signaling pathways, which may contribute to the development of new targets for the treatment of prostate cancer.
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