Estrogen Receptor Alpha Proteostasis in Breast Cancer

描述（由申请方提供）：乳腺癌临床管理中的一个持续挑战是为什么某些表达雌激素受体-α（ERα）的ER+肿瘤患者不能从激素治疗中获益。ERα蛋白稳态是细胞通过调节受体水平来控制激素敏感性和依赖性的基本过程。虽然ER 1蛋白质稳态的破坏导致受体功能的病理性获得和丧失，绕过雌激素和抗雌激素的控制，但控制ERα蛋白质稳态的信号和机制及其对治疗反应的影响仍知之甚少。通过增加我们对乳腺癌中ERα蛋白稳态的理解，拟议的研究旨在提高我们控制和预测ER+疾病患者对基于乳腺癌的治疗反应的能力。我们已发表的和初步的研究揭示了乳腺癌细胞中调节ERα蛋白稳态的三个新领域，包括控制ERα蛋白在癌细胞中的稳定性和功能的新机制见解，肿瘤微环境的贡献，以及通过免疫组织化学严格定量肿瘤样品中ERα蛋白水平的新应用。这些研究支持细胞内在和外在因素控制乳腺肿瘤细胞中ERα蛋白从而有助于治疗结果的假设。在目标1中，我们专注于ERα蛋白稳定性的内在机制，重点是新发现的肽基脯氨酰异构酶Pin 1的调节。在目标2中，我们将创新的生物工程技术应用于通过原代患者成纤维细胞研究乳腺癌细胞中ERα蛋白的调节。最后，在目标3中，我们使用AQUA技术在患者肿瘤样本的复杂环境中测试我们的分子和细胞分析预测，以建立Pin 1和ERα水平与治疗结果的关系。这项研究有望大大扩展我们对控制ER 1蛋白的机制的了解，从而加强未来的策略，将激素疗法的益处扩展到更多的女性。

DESCRIPTION (provided by applicant): A persistent challenge in the clinical management of breast cancer is why certain patients with ER+ tumors that express estrogen receptor-α (ERα) do not benefit from hormonal therapies. ERα proteostasis is fundamental process by which cells control sensitivity and dependence on hormones through the regulation of receptor levels. While disruptions of ER1 proteostasis result in pathological gains and losses of receptor function that bypass control by estrogens and antiestrogens, the signals and mechanisms that control ERα proteostasis and their impact on therapeutic response are poorly understood. By increasing our understanding of ERα proteostasis in breast cancer, the proposed studies seek to improve our ability to control and predict response to hormone-based therapies in patients with ER+ disease. Our published and preliminary studies shed light on three new areas regulating ERα proteostasis in breast cancer cells, including new mechanistic insight controlling ERα protein stability and function in cancer cells, contributions of the tumor microenvironment, and a new application to rigorously quantify ERα protein levels by immunohistochemistry in tumor samples. These studies support the hypothesis that both cell-intrinsic and extrinsic factors control ERα protein in breast tumor cells thereby contributing to therapeutic outcomes. In Aim 1, we focus on intrinsic mechanisms governing ERα protein stability with emphasis on newly discovered regulation by the peptidyl prolyl isomerase, Pin1. In Aim 2, we apply innovative bioengineering technologies to the study of ERα protein regulation in breast cancer cells by primary patient fibroblasts. Finally, in Aim 3, we test predictions from our molecular and cellular analysis in the complex environment of patient tumor samples using AQUA technology to establish the relationship of Pin1 and ERα levels to therapy outcomes. This research is expected to considerably expand our knowledge of the mechanisms controlling ER1 protein and thereby enhance future strategies to extend the benefit of hormonal therapies to a greater number of women.