Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and Secondary Effects.
Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and Secondary Effects.
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DOI：
10.1158/0008-5472.can-20-1171
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发表时间：
2021-02-01
期刊：
影响因子：
11.2
通讯作者：
Gertz J
中科院分区：
文献类型：
--
作者：
Arnesen S;Blanchard Z;Williams MM;Berrett KC;Li Z;Oesterreich S;Richer JK;Gertz J
虽然患有表达雌激素受体α（ER）的肿瘤的乳腺癌患者通常对阻断ER活性的激素治疗反应良好，但大量患者复发。大约30%的这些复发性疾病在ER的配体结合结构域（LBD）中具有激活突变，其已被证明赋予配体非依赖性功能。然而，除了雌激素独立性之外，关于突变ER的影响还有很多尚不清楚。为了研究突变型ER的分子效应，我们开发了多个针对最常见的LBD突变Y537S和D538G的同基因ER突变细胞系。这些突变诱导了数千个基因的差异表达，其中大多数是突变等位基因特异性的，并且在野生型细胞的雌激素处理后未观察到。这些突变体特异性基因在其他实验室开发的ER突变株系中表现出一致的差异表达。长期雌激素暴露的野生型细胞仅表现出这些转录变化中的一些，这表明突变的ER引起新的调节作用，而不仅仅是由于恒定的活性。虽然ER突变对ER基因组结合的影响很小，但除了配体独立性外，ER突变在染色质可及性方面具有实质性差异。突变体ER与大约四分之一的富含其他DNA结合因子（包括FOXA 1、CTCF和OCT 1）的富含mu的可接近区域结合。总的来说，我们的研究结果表明，突变ER引起几个一致的影响基因表达，间接和通过恒定的活动。
While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER activity, a significant number of patients relapse. Approximately 30% of these recurrences harbor activating mutations in the ligand binding domain (LBD) of ER, which have been shown to confer ligand-independent function. However, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate the molecular effects of mutant ER, we developed multiple isogenic ER mutant cell lines for the most common LBD mutations, Y537S and D538G. These mutations induced differential expression of thousands of genes, the majority of which were mutant allele-specific and were not observed upon estrogen treatment of wildtype cells. These mutant-specific genes showed consistent differential expression across ER mutant lines developed in other laboratories. Wildtype cells with long-term estrogen exposure only exhibited some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations exhibited minor effects on ER genomic binding, with the exception of ligand independence, ER mutations conferred substantial differences in chromatin accessibility. Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity.