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.

项目摘要/摘要一半的雌激素受体（ERα）阳性乳腺癌患者接受内分泌疗法的治疗表现出内在的或获得的耐药性。这些患者中有三分之一出现含有ERαY537S的转移性肿瘤突变。该突变导致ERα的组成活性并改变了ERα相关基因表达。先前的研究表明，ERα和孕酮受体（PR）进行复杂的相互作用涉及ERα和PR转录因子活性的相互调节，称为ERα/PR串扰。那，仅在ERα/PR阳性乳房中靶向两个核接收器可能会有热值癌症。但是，初步数据表明，在ERαY537s的背景下，ERα/PR串扰发生了变化。可能导致耐药性。尽管与ERαY537和联合ERα/PR疗法的功效已经独立评估，尚未表征 ERαY537S对ERα/PR串扰的影响或ERα/PR靶向疗法对 ERα/PR串扰在ERαY537的背景下。该提议的目的是确定最常见的是ERα/PR串扰上的耐药性ERαY537S突变和结果转录活性，并阐明这种独特的相互作用如何导致ERα-的内分泌疗法抗性阳性乳腺癌。先前的研究确定了ERα联合ERα/PR拮抗作用的协同作用 WT癌细胞，其中合并的治疗导致体内肿瘤消退。相反，初步数据表明用ERα和PR拮抗剂的ERαY537S肿瘤的治疗显着导致体内肿瘤增殖的增加。由于先前的研究突出了基因的重大改变与ERαY537S相关的表达，可能会变化ERα和PR驱动基因表达驱动对ERα和PR拮抗剂的反应改变。我的中心假设是ERαY537S改变了 ERα和PR的转录因子活性，导致抗Serm抗性乳房中基因表达失调癌症。该假设将以以下特定目的进行评估： 1。确定激活的ERαY537S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的效率（Serm和Serm和 Sprms）在治疗ERαY537S肿瘤的患者衍生模型中。了解ERαY537s在改变基因表达并减少对Serm和Serm的反应中的作用 SPRM治疗将提供有关这些肿瘤为何耐心治疗的原因的理解并将提出治疗的替代靶标。