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

• 批准号: 10153330
• 负责人: Rosemary J Huggins
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/10153330
• 关键词: Affect; Automobile Driving; Biological; Biological Assay; Breast Cancer Patient; Cell Death; Cell Line; Cell Survival; Cells; ChIP-on-chip; ChIP-seq; Characteristics; Combined Modality Therapy; Complex; Data; Data Set; Disease; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Growth; 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; Public Health; Regulation; Regulator Genes; Research; Resistance; Role; Selective Estrogen Receptor Modulators; Site; Structure; Therapeutic; United States National Institutes of Health; alternative treatment; cancer cell; hormone therapy; improved; in vivo; malignant breast neoplasm; mutant; patient derived xenograft model; progesterone receptor positive; prophylactic; protein expression; receptor; receptor binding; receptor function; response; screening; single-cell RNA sequencing; standard of care; targeted treatment; therapy development; therapy resistant; transcription factor; treatment response; tumor; tumor growth; tumor xenograft

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.

项目总结/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为内源性 或获得性治疗抵抗。这些患者中有三分之一存在含有ERα Y 537 S的转移性肿瘤 突变。该突变导致ERα的组成性活性和改变的ERα相关基因表达。 先前的研究表明ERα和孕激素受体（PR）参与复杂的相互作用 涉及ERα和PR转录因子活性的相互调节，称为ERα/PR串扰。因此，在本发明中， 同时靶向两种核受体对ERα/PR阳性乳腺癌可能有治疗价值 癌的然而，初步数据表明，ERα/PR串扰在ERα Y 537 S的背景下发生了改变， 可能导致了治疗抵抗尽管ERα Y 537 S和ER α Y 537 S的组成性活性与ERα Y 537 S和ER α Y 537 S的组成性活性相关，但ER α Y 537 S的组成性活性与ERα Y 537 S和ER α Y 537 S的组成性活性相关，而ER α Y 537 S的组成性活性与ER α Y 537 S的组成性活性无关。 ERα/PR联合治疗的疗效已被独立评估，但仍有待表征 ERα Y 537 S对ERα/PR串扰的影响或ERα/PR靶向治疗对ERα/PR串扰的特异性影响。 ERα Y 537 S背景下的ERα/PR串扰。本提案的目的是确定 最常见的治疗耐药ERα Y 537 S突变对ERα/PR串扰和由此产生的 转录活性，并阐明这种独特的相互作用如何导致ERα- 乳腺癌阳性。先前的研究证实了ERα/PR联合拮抗在ERα中的协同作用。 WT癌细胞，其中组合治疗导致体内肿瘤消退。相反，初步数据 提示ERα和PR拮抗剂联合治疗ERα Y 537 S肿瘤可显著降低ERα Y 537 S的表达， 增加体内肿瘤增殖。由于先前的研究强调了基因的重大改变， 与ERα Y 537 S相关的表达，可能是ERα和PR驱动的基因表达的变化 驱动对ERα和PR拮抗剂的反应改变。我的中心假设是ERα Y 537 S改变了 ERα和PR的转录因子活性，导致SERM耐药乳腺癌中基因表达失调 癌将根据以下具体目标对该假设进行评估： 1.确定激活ERα Y 537 S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）在治疗ERα Y 537 S肿瘤的患者来源模型中的作用。 了解ERα Y 537 S在改变基因表达和降低对SERM的反应中的作用， SPRM治疗将有助于了解这些肿瘤对标准治疗耐药的原因 并将另外提出用于治疗的替代靶点。