Estrogen Receptor Alpha Proteostasis in Breast Cancer

描述(申请人提供)：乳腺癌临床治疗中的一个长期挑战是为什么某些ER+肿瘤表达雌激素受体-1(ER1)的患者不能从激素治疗中受益。ER1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ER1蛋白稳态的破坏会导致受体功能的病理性获得和丧失，从而绕过雌激素和抗雌激素的控制，但控制ER1蛋白稳态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，拟议的研究试图提高我们控制和预测ER+疾病患者对激素治疗的反应的能力。我们已发表的和初步的研究揭示了调控乳腺癌细胞ER1蛋白稳定的三个新领域，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，以及通过免疫组织化学在肿瘤样本中严格定量ER1蛋白水平的新应用。这些研究支持这样的假设，即细胞内在和外在因素都控制着乳腺肿瘤细胞中的ER1蛋白，从而有助于治疗结果。在目标1中，我们专注于控制ER1蛋白稳定性的内在机制，重点是新发现的由肽基脯氨酰异构酶Pin1调节的机制。在目标2中，我们应用创新的生物工程技术来研究原发患者成纤维细胞对乳腺癌细胞ER1蛋白的调控。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的预测，以建立Pin1和ER1水平与治疗结果的关系。这项研究有望极大地扩展我们对ER1蛋白控制机制的了解，从而加强未来的战略，将激素疗法的好处扩大到更多的女性。

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.