Beta-catenin and Androgen Signaling in Prostate Cancer

描述(申请人提供)：像大多数其他癌症一样，前列腺癌的发生涉及一个从癌前细胞到细胞的多步骤发展过程，这些细胞在局部以不受调控的方式增殖，然后转移。在这种疾病的转移阶段，肿瘤细胞经常失去细胞间的接触，并具有更具侵袭性的生长表型。雄激素消融治疗前列腺癌的观察表明，雄激素信号通路在前列腺癌的生长和发展中起着重要的作用。雄激素的促生长作用主要是通过雄激素受体(AR)介导的。前列腺癌晚期常可观察到细胞膜上E-钙粘附素的丢失，这与肿瘤细胞侵袭性增加及临床预后不良密切相关。β-连环蛋白通常定位于细胞膜、胞浆和胞核，在细胞间黏附和信号转导中具有双重作用。最近，我们展示了β-连环蛋白和AR之间的一种特殊的蛋白质-蛋白质相互作用。与类固醇受体辅因子1(SRC1)不同，β-连环素以配体依赖的方式选择性地与AR结合，但不与其他类固醇激素受体结合。AR和β-catenin之间的相互作用区域被映射到AR的配体结合域，以及跨越β-catenin的犰螂重复序列1-6的N-末端和中心区。通过这种特定的相互作用，β-连环蛋白增强了前列腺癌细胞中AR的配体依赖活性。这些数据表明，β-连环蛋白是AR的辅助激活因子，可能在AR介导的细胞生长和存活中发挥关键作用。有证据表明，前列腺癌晚期常可观察到E-钙粘蛋白表达缺失，β-连环蛋白是AR的辅助激活因子，可能在AR介导的细胞生长和存活中发挥关键作用。本研究的主要目的是进一步研究AR和β-连环蛋白之间的相互作用，以了解β-连环蛋白在前列腺癌发生发展中的生物学作用及其与雄激素信号的相互作用。最终，我们希望确定相互作用的关键区域(目标1)，确定β-连环蛋白在前列腺癌细胞中的生物学作用及其与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控(目标3)。这项研究的长期目标是确定可以针对前列腺癌治疗的新步骤。

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.