Beta-catenin and Androgen Signaling in Prostate Cancer

描述（由申请人提供）：与大多数其他癌症一样，前列腺癌发生涉及从癌前细胞到以不受调节的方式局部增殖然后转移的细胞的多步进展。在这种疾病的转移阶段，肿瘤细胞通常失去细胞-细胞接触，并具有更具侵略性的生长表型。前列腺癌的雄激素消融治疗的观察表明，雄激素信号通路在前列腺癌的生长和进展中是重要的。雄激素的促生长作用主要通过雄激素受体（AR）介导。在前列腺癌的晚期阶段经常观察到细胞膜上的E-钙粘蛋白的丢失，这与肿瘤细胞的侵袭行为增加和临床结果差密切相关。β-连环蛋白通常定位于细胞膜、细胞质和细胞核中，在细胞间粘附和信号转导中起双重作用。最近，我们证明了β-连环蛋白和AR之间的特异性蛋白质-蛋白质相互作用。与类固醇受体辅因子1（SRC 1）不同，β-连环蛋白以配体依赖性方式选择性结合AR，但不结合其他类固醇激素受体。AR和β-连环蛋白之间的相互作用结构域被映射到AR的配体结合结构域和β-连环蛋白的N-末端和跨越犰狳重复序列1-6的中心区域。通过这种特异性相互作用，β-连环蛋白增强了前列腺癌细胞中AR的配体依赖性活性。这些数据表明，β-连环蛋白是AR的共激活因子，并可能在AR介导的细胞生长和存活中发挥关键作用。基于在前列腺癌的晚期经常观察到E-钙粘蛋白表达丧失的证据，β-连环蛋白是AR的共激活剂，并且可能在AR介导的细胞生长和存活中起关键作用。我们的主要目标是进一步研究AR和β-连环蛋白之间的相互作用，以了解β-连环蛋白的生物学作用及其与前列腺癌肿瘤发生中雄激素信号传导的串扰。最终，我们希望确定相互作用的关键区域（目标1），确定β-连环蛋白的生物学作用及其与前列腺癌细胞中AR的相互作用（目标2），并确定β-连环蛋白的生理意义及其在前列腺癌发病机制中的调节（目标3）。这项研究的长期目标是确定可用于治疗前列腺癌的新步骤。

DESCRIPTION (provided by applicant): 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. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). Loss of E-cadherin from the cell membrane is frequently observed in the late stages of prostate cancer, which is closely associated with the increased invasive behavior of tumor cells and a poor clinical outcome. Beta-catenin, normally localized in the cell membrane, in the cytoplasm and in the nucleus, plays dual roles in intercellular adhesion and signal transduction. Recently, we demonstrated a specific protein-protein interaction between beta-catenin and AR. Unlike the steroid receptor cofactor 1 (SRC1), beta-catenin selectively binds to AR in a ligand-dependent manner, but does not bind to other steroid hormone receptors. The interaction domains between AR and beta-catenin are mapped to the ligand binding domain of AR and the N-terminus and central region spanning the armadillo repeats 1-6 of beta-catenin. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. These data suggest that beta-catenin is a coactivator of the AR and may play a critical role in AR mediated cell growth and survival. Based on the evidence that loss of E-cadherin expression is frequently observed in the advanced stages of prostate cancer, beta-catenin is a coactivator of the AR and may play a critical role in AR mediated cell growth and survival. Our major objective in this proposal is to further characterize the interaction between AR and beta-catenin in order to understand the biological roles of beta-catenin and its crosstalk with androgen signaling in the tumorigenesis of prostate cancer. Ultimately, we wish to identify the key regions for the interaction (Aim 1), determine the biological roles of beta-catenin and its interaction with AR in prostate cancer cells (Aim 2), and define physiological significance of beta-catenin and its regulation in the pathogenesis of prostate cancer (Aim 3). The long-term goal of this study is to identify new steps that can be targeted for the treatment of prostate cancer.