Beta-catenin and Androgen Signaling in Prostate Cancer

描述（由申请人提供）：像大多数其他癌症一样，前列腺癌的发生涉及从癌前细胞到细胞的多步骤进展，这些细胞以不受调节的方式局部增殖，然后转移。在这种疾病的转移期，肿瘤细胞经常失去细胞间的接触，并具有更具侵略性的生长表型。雄激素消融术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进展中起重要作用。雄激素的促生长作用主要是通过雄激素受体（AR）介导的。在前列腺癌晚期，细胞膜上E-cadherin的丢失是常见的，这与肿瘤细胞侵袭性行为增加和临床预后差密切相关。-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 -连环蛋白与AR之间的特异性蛋白-蛋白相互作用。与类固醇受体辅助因子1 （SRC1）不同，β -连环蛋白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与β -连环蛋白之间的相互作用域被定位到AR的配体结合域和横跨犰狳重复β -连环蛋白1-6的n端和中心区域。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，可能在AR介导的细胞生长和存活中起关键作用。有证据表明，E-cadherin的表达缺失在前列腺癌晚期经常观察到，β -catenin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。我们的主要目的是进一步表征AR和β -catenin之间的相互作用，以了解β -catenin及其与雄激素信号的串扰在前列腺癌肿瘤发生中的生物学作用。最终，我们希望确定相互作用的关键区域（Aim 1），确定β -catenin及其在前列腺癌细胞中与AR的相互作用的生物学作用（Aim 2），并确定β -catenin及其在前列腺癌发病机制中的调节的生理意义（Aim 3）。这项研究的长期目标是确定可以靶向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.