Beta Catenin in Prostate Cancer

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DESCRIPTION (provided by applicant): Beta-catenin is a component of the Wnt signaling pathway that is disrupted by oncogenic mutations in many cancer types. We first demonstrated that beta-catenin was mutated in a subset of prostate cancer specimens. Emerging data from other laboratories have confirmed our findings and identified mutations in other components of the Wnt signaling pathway such as APC in prostate cancer. In prostate cancer cells mutant beta-catenin can potentiate androgen receptor (AR) signaling and broaden ligand specificity. Since increased AR activity and response to an expanded range of steroid hormones is a hallmark of advanced prostate cancer, beta-catenin mutations appear to be an additional mechanism by which prostate cancer cells enhance AR activity. This finding may have clinical implications for determining apropriate second-line hormonal therapy for prostate cancer patients. We now propose to elucidate the details of the direct intermolecular interactions between beta-catenin and androgen receptor. Our preliminary data indicate that beta-catenin binds to the AR ligand-binding domain. Moreover, LXXLL peptide motifs in the beta-catenin armadillo repeat region that resemble motifs in p160 steroid hormone coactivator molecules are important for beta-catenin/ AR interaction. Using a mammalian two-hybrid assay we will determine the regions of androgen receptor bound by beta-catenin and we will determine the regions of beta-catenin that bind androgen receptor. Using recombinant proteins we will demonstrate the direct physical interaction between AR and beta-catenin. We will also determine the ligand-dependence of this binding and the spectrum of ligands that support the interaction. We will determine if beta-catenin affects the interaction of androgen receptor with ligand by measuring dissociation of different ligands from androgen receptor. Lastly, we will determine the mechanism by which beta-catenin synergizes with p160 steroid receptor coactivator proteins to increase AR activity. These experiments will clearly establish as interaction between the Wnt signaling and steroid receptor pathways and thereby describe a new mechanism for prostate cancer progression, which is often dependent on enhancement of AR activity.