Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER⁺) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

中文翻译：

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ESR1 激活突变的等位基因特异性染色质募集和治疗漏洞。

在大量内分泌治疗耐药的转移性 ER 阳性（ER ⁺) 乳腺癌。我们研究了含有临床相关 ER 突变的乳腺癌模型中的染色质募集、转录网络和遗传脆弱性。这些突变体既表现出模拟雌二醇结合的野生型 ER 的配体独立功能，也表现出促进促转移表型的等位基因特异性新形态特性。对全基因组 ER 结合位点的分析确定了介导等位基因特异性转录程序的突变 ER 独特募集。遗传筛选确定了对由突变体驱动的配体非依赖性生长必不可少的基因。这些研究提供了对由 ER 突变和潜在治疗靶点产生的内分泌治疗耐药机制的见解。