Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1⁺ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1–chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

中文翻译：

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人类乳腺肿瘤中的雌激素受体 1 染色质分析揭示了患者间的高度异质性，其中风险 SNP 和大多数保守区域的增强子活性富集


雌激素受体 1（ESR1；也称为 ERα，由 ESR1 基因编码）是腔内乳腺癌的主要驱动因素和主要药物靶点。 ESR1 染色质结合在细胞系和有限数量的人类肿瘤中使用样本之间共享的共有峰进行了广泛研究。然而，人们对 ESR1 染色质作用的肿瘤间异质性及其生物学意义知之甚少。在这里，我们使用来自 70 个 ESR1 ⁺ 乳腺癌的大量 ESR1 ChIP-seq 数据来探索 ESR1 DNA 结合的患者间异质性，以揭示 ESR1 作用的惊人的肿瘤间异质性。值得注意的是，共同共享的 ESR1 位点显示出最高的雌激素驱动的增强子活性，并且最参与长程染色质相互作用。此外，最常见的 ESR1 占据增强子富含乳腺癌风险 SNP 位点。我们通过实验证实 SNV 会影响 ESR1 及其先锋因子 FOXA1 的染色质结合潜力。最后，在 TCGA 乳腺癌队列中，我们可以确认这些变异与目标基因表达差异相关。总的来说，我们揭示了乳腺癌中ESR1-染色质相互作用在高度异质的肿瘤间ESR1景观中的自然层次结构，其中最常见的共享区域是最活跃的，并受到乳腺癌发展的种系功能风险SNP的影响。