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-1（ER 1）的ER+肿瘤患者不能从激素治疗中获益。ER 1蛋白稳态是细胞通过调节受体水平来控制对激素的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ER 1蛋白质稳态的信号和机制及其对治疗反应的影响知之甚少。通过增加我们对乳腺癌中ER 1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三个新的领域调节乳腺癌细胞中的ER 1蛋白稳态，包括控制ER 1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量化ER 1蛋白水平的新应用。这些研究支持了这样的假设，即细胞内在和外在因素控制乳腺肿瘤细胞中的ER 1蛋白，从而有助于治疗结果。在目的1中，我们专注于内在机制，ER 1蛋白质的稳定性，重点是新发现的调节肽脯氨酰异构酶，Pin 1。在目标2中，我们将创新的生物工程技术应用于研究乳腺癌细胞中原代患者成纤维细胞的ER 1蛋白调节。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ER 1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。 公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因。激素疗法是一种有效且耐受性良好的治疗方法，但并非所有女性都能从这种疗法中受益。该提案的目的是更好地了解细胞如何操纵激素治疗的靶点（ER 1），以保持对激素和激素治疗的敏感性。所获得的知识可以提高我们预测和控制乳腺癌治疗反应的能力，从而将这些治疗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-1 (ER1) do not benefit from hormonal therapies. ER1 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 ER1 proteostasis and their impact on therapeutic response are poorly understood. By increasing our understanding of ER1 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 ER1 proteostasis in breast cancer cells, including new mechanistic insight controlling ER1 protein stability and function in cancer cells, contributions of the tumor microenvironment, and a new application to rigorously quantify ER1 protein levels by immunohistochemistry in tumor samples. These studies support the hypothesis that both cell-intrinsic and extrinsic factors control ER1 protein in breast tumor cells thereby contributing to therapeutic outcomes. In Aim 1, we focus on intrinsic mechanisms governing ER1 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 ER1 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 ER1 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. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer death in women. Hormonal therapies are an effective and well-tolerated treatment but not all women benefit from this therapy. The objectives of this proposal are to better understand how cells manipulate the target of hormonal therapies (ER1) to maintain sensitivity to hormones and hormonal therapies. The knowledge gained could enhance our ability to predict and to control therapy responsiveness in breast cancers and thereby extend the benefit of these treatments to a greater number of women.