Estrogen Receptor Alpha Proteostasis in Breast Cancer

描述（由申请人提供）：乳腺癌临床管理中一个持续的挑战是为什么某些表达雌激素受体-1 （ER1）的ER+肿瘤患者不能从激素治疗中获益。ER1蛋白抑制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ER1蛋白平衡的破坏会导致绕过雌激素和抗雌激素控制的受体功能的病理获得和丧失，但控制ER1蛋白平衡的信号和机制及其对治疗反应的影响尚不清楚。通过增加我们对乳腺癌中ER1蛋白平衡的了解，拟议的研究旨在提高我们控制和预测ER+疾病患者对激素治疗反应的能力。我们发表的和初步的研究揭示了乳腺癌细胞中ER1蛋白稳态调节的三个新领域，包括控制癌细胞中ER1蛋白稳定性和功能的新机制，肿瘤微环境的贡献，以及通过免疫组化严格量化肿瘤样本中ER1蛋白水平的新应用。这些研究支持了一种假设，即细胞内源性和外源性因素控制着乳腺癌细胞中的ER1蛋白，从而促进了治疗结果。在Aim 1中，我们关注ER1蛋白稳定性的内在机制，重点关注新发现的肽基脯氨酸异构酶Pin1的调节作用。在Aim 2中，我们将创新的生物工程技术应用于原代患者成纤维细胞对乳腺癌细胞中ER1蛋白调控的研究。最后，在Aim 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Pin1和ER1水平与治疗结果的关系。这项研究有望大大扩展我们对ER1蛋白控制机制的认识，从而增强未来的策略，将激素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.