Estrogen Receptor Alpha Proteostasis in Breast Cancer

乳腺癌中雌激素受体α蛋白稳态

基本信息

批准号：
8706825
负责人：
Elaine T Alarid
金额：
$ 30.15万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706825
关键词：
Accounting Amino Acids Area Binding Sites Biochemical Biological Assay Biology Biomedical Engineering Breast Cancer Cell Bypass Cancer Etiology Cancer Patient Cells Cessation of life Clinical Clinical Management Complex Data Dependence Dependency Development Devices Disease Environment Estrogen Antagonists Estrogen Receptor 1 Estrogen Receptor Modulators Estrogen Receptor alpha Estrogen Receptors Estrogens Failure Fibroblasts Future Genetic Transcription Goals Growth Hormones Human Immunohistochemistry In Vitro Isomerism Knowledge Laboratories Lead Light Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Methodology Microfluidics Molecular Molecular Conformation Molecular Target Outcome Patients Peptidylprolyl Isomerase Phosphorylation Process Property Proteins Publishing Regulation Research Resistance Sampling Signal Pathway Signal Transduction Steroid Receptors Tamoxifen Technology Testing Therapeutic Tissue Microarray Treatment Efficacy Ubiquitination Woman base cancer cell cancer therapy cellular engineering cofactor cohort conformer estrophilin hormone sensitivity hormone therapy improved innovation insight malignant breast neoplasm neoplastic cell novel overexpression protein function receptor receptor function response steroid hormone receptor therapy outcome tumor tumor microenvironment tumor progression

项目摘要

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.

描述（由申请人提供）：乳腺癌临床治疗中的一个持续挑战是为什么某些表达雌激素受体 1 (ER1) 的 ER+ 肿瘤患者无法从激素治疗中受益。 ER1 蛋白质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 蛋白质稳态的破坏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 ER1 蛋白质稳态的了解，拟议的研究旨在提高我们控制和预测 ER+ 疾病患者对激素疗法反应的能力。我们发表的初步研究揭示了调节乳腺癌细胞中 ER1 蛋白稳态的三个新领域，包括控制癌细胞中 ER1 蛋白稳定性和功能的新机制见解、肿瘤微环境的贡献以及通过以下方法严格量化 ER1 蛋白水平的新应用：肿瘤样本中的免疫组织化学。这些研究支持这样的假设：细胞内在和外在因素都控制乳腺肿瘤细胞中的 ER1 蛋白，从而有助于治疗结果。在目标 1 中，我们重点关注控制 ER1 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 Pin1 的调节。在目标 2 中，我们应用创新的生物工程技术来研究原发性患者成纤维细胞对乳腺癌细胞中 ER1 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。这项研究预计将大大扩展我们对 ER1 蛋白控制机制的了解，从而增强未来的策略，将激素疗法的益处惠及更多女性。