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

项目摘要/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为内分泌 或后天的治疗抵抗力。这些患者中有三分之一患有含有ERαY537S的转移性肿瘤 突变。这种突变导致ERα的结构性活性，并改变ERα相关基因的表达。 以前的研究表明，ERα和孕激素受体(PR)参与了复杂的相互作用 涉及ERα和PR转录因子活性的相互调节，称为ERα/PR串扰。因此， ERα/PR阳性乳腺同时靶向两种核受体可能具有治疗价值 癌症。然而，初步数据表明，ERα/PR串扰在ERαY537S的背景下发生了改变， 可能会导致治疗抵抗。尽管ERαY537S和 ER、α/PR联合治疗的疗效已被独立评估，尚未确定其特征 ERαY537S对ERα/PR串扰的影响或ERα/PR靶向治疗对 ERαY537S环境中的ERα/PR串扰。这项建议的目的是确定 ERαY537S最常见的耐药突变与ERα/PR串扰及由此产生的 转录活性，并阐明这种独特的相互作用如何导致内分泌治疗抵抗的ERα- 阳性乳腺癌。已有研究证实ERα/PR联合拮抗对ERα有协同作用 WT癌细胞，在体内联合治疗可导致肿瘤消退。相反，初步数据 提示ERαY537S肿瘤联合ER、α和PR拮抗剂治疗效果显著 体内肿瘤增殖增加。因为之前的研究已经强调了基因的显著变化 与ERαY537S相关的表达，很可能同时改变了ERα和PR驱动的基因表达 驱动对ER、α和PR拮抗剂的改变反应。我的中心假设是ERαY537S改变了 ER、α和PR转录因子活性导致耐药乳腺组织基因表达异常 癌症。这一假设将以以下具体目标进行评估： 1.确定激活的ERαY537S点突变如何影响ERα的转录活性和改变 ERα/PR串音。 2.评估各种选择性雌孕激素受体调节剂(SERM和SERM)的疗效 SPRM)用于治疗患者衍生的ERαY537S肿瘤模型。 了解ERαY537S在改变基因表达和降低对SERM和 SPRM治疗将有助于理解为什么这些肿瘤对标准治疗具有抵抗力。 并将另外提出治疗的替代靶点。

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.