Contribution of ERa/PR Crosstalk to Endocrine Therapy Resistance in the Context of ERa-Y537S

ERa-Y537S 背景下 ERa/PR 串扰对内分泌治疗耐药的贡献

基本信息

批准号：
10576898
负责人：
Rosemary J Huggins
金额：
$ 4.77万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10576898
关键词：
Affect Automobile Driving Biological Biological Assay Breast Cancer Patient Cell Death Cell Line Cell Survival Cells ChIP-seq Characteristics Combined Modality Therapy Complex Data Data Set Disease Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Growth Heterozygote In Vitro Ligand Binding Domain MCF7 cell Measures Mediating Mission Modality Modeling Mus Mutation Neoplasm Metastasis Nuclear Receptors Organoids Patients Point Mutation Primary Neoplasm Progesterone Receptors Proliferating Public Health Receptor Cross-Talk Regulation Regulator Genes Research Resistance Role Selective Estrogen Receptor Modulators Site Therapeutic United States National Institutes of Health alternative treatment antagonist cancer cell efficacy evaluation hormone therapy improved in vivo malignant breast neoplasm mutant patient derived xenograft model progesterone receptor positive prophylactic protein expression receptor receptor binding response screening single-cell RNA sequencing standard of care targeted treatment therapy development therapy resistant transcription factor treatment response tumor tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY/ABSTRACT Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies manifest intrinsic or acquired therapy resistance. One-third of these patients present with metastatic tumors containing ERα Y537S mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression. Previous research suggests that ERα and the progesterone receptor (PR) engage in complex interactions involving reciprocal regulation of ERα and PR transcription factor activity known as ERα/PR crosstalk. Thus, there may be therapeutic value in targeting both nuclear receptors simultaneously in ERα/PR-positive breast cancers. However, preliminary data suggests that ERα/PR crosstalk is altered in the context of ERα Y537S, likely contributing to therapy resistance. Although the constitutive activity associated with ERα Y537S and the efficacy of combined ERα/PR therapies have independently been assessed, there has yet to be characterization of the effects of ERα Y537S on ERα/PR crosstalk or the specific effects of ERα/PR-targeted therapies on ERα/PR crosstalk in the context of ERα Y537S. The objective of this proposal is to determine the effects of the most commonly occurring, treatment-resistant ERα Y537S mutation on ERα/PR crosstalk and resultant transcriptional activity, and to elucidate how this unique interaction leads to endocrine therapy resistance in ERα- positive breast cancer. Previous research identified a synergistic effect of combined ERα/PR antagonism in ERα WT cancer cells, where combined treatment results in tumor regression in vivo. Conversely, preliminary data suggests that treatment of ERα Y537S tumors with combined ERα and PR antagonists results in significantly increased tumor proliferation in vivo. As previous research has highlighted a significant alteration in gene expression associated with ERα Y537S, it is likely that changes to both ERα- and PR-driven gene expression drive the altered response to ERα and PR antagonists. My central hypothesis is that ERα Y537S alters the transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. This hypothesis will be assessed with the following Specific Aims: 1. Determine how the activating ERα Y537S point mutation affects ERα transcriptional activity and alters ERα/PR crosstalk. 2. Assess the efficacy of various selective estrogen and progesterone receptor modulators (SERMs and SPRMs) in treating patient-derived models of ERα Y537S tumors. Understanding the role of ERα Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will additionally suggest alternative targets for treatment.

项目概要/摘要接受内分泌治疗的雌激素受体（ERα）阳性乳腺癌患者中有一半表现出内在的这些患者中有三分之一患有含有 ERα Y537S 的转移性肿瘤。这种突变导致 ERα 的组成型活性和 ERα 相关基因表达的改变。先前的研究表明 ERα 和孕激素受体 (PR) 存在复杂的相互作用 ERα 和 PR 转录因子活性的相互调节称为 ERα/PR 涉及串扰。同时针对 ERα/PR 阳性乳腺中的两种核受体可能具有治疗价值然而，初步数据表明 ERα/PR 串扰在 ERα Y537S 的背景下发生了改变，尽管与 ERα Y537S 相关的组成活性和 ERα/PR 联合疗法的疗效已被独立评估，但尚待表征 ERα Y537S 对 ERα/PR 串扰的影响或 ERα/PR 靶向治疗对 ERα Y537S 背景下的 ERα/PR 串扰该提案的目的是确定 ERα Y537S 的影响。 ERα/PR 串扰及其结果中最常见的治疗耐药性 ERα Y537S 突变转录活性，并阐明这种独特的相互作用如何导致 ERα-内分泌治疗耐药先前的研究发现 ERα/PR 联合拮抗作用在 ERα 中具有协同作用。 WT 癌细胞，其中联合治疗导致体内肿瘤消退，初步数据。表明联合 ERα 和 PR 拮抗剂治疗 ERα Y537S 肿瘤可显着正如先前的研究强调了基因的显着改变。与 ERα Y537S 相关的表达，很可能 ERα 和 PR 驱动的基因表达都发生变化驱动对 ERα 和 PR 拮抗剂的反应改变我的中心假设是 ERα Y537S 改变了 ERα 和 PR 的转录因子活性，导致 SERM 耐药乳腺基因表达失调该假设将通过以下具体目标进行评估： 1. 确定激活的 ERα Y537S 点突变如何影响 ERα 转录活性并改变 ERα/PR 串扰。 2. 评估各种选择性雌激素和孕激素受体调节剂（SERM 和 SPRM）用于治疗源自患者的 ERα Y537S 肿瘤模型。了解 ERα Y537S 在改变基因表达和减少对 SERM 的反应中的作用 SPRM 治疗将有助于理解为什么这些肿瘤对标准护理治疗有抵抗力并将另外建议替代治疗目标。