Chromatin profile-based identification of a novel ER-positive breast cancer subgroup with reduced ER-responsive element accessibility

Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy. 42 breast cancer samples collected by core needle biopsies from surgical specimens were objected to ATAC-seq analysis. ***Please note that raw data is not provided since the submitter have obtained informed consent that does not presuppose registration of genomic sequence data in public databases.

雌激素受体（Estrogen Receptor，ER）信号通路依赖的癌细胞增殖，是ER阳性乳腺癌（Breast Cancer，BC）的核心特征之一。抑制ER功能是治疗ER阳性肿瘤的标准有效方案，但约20%的ER阳性BC患者会出现早期或晚期复发。本研究基于“ER信号通路周围表观遗传状态的固有差异是内分泌治疗耐药的潜在机制”这一假说，从表观遗传学角度探究了肿瘤间异质性。我们对42例BC样本的染色质可及性数据进行了分析，其中包括35例ER阳性人表皮生长因子受体2（Human Epidermal Growth Factor Receptor 2，HER2）阴性样本与7例三阴性乳腺癌样本，鉴定出一类具有独特染色质可及性特征的ER阳性BC亚群，其特征为ER应答元件（ER-responsive Elements，EREs）的可及性降低。该亚群在癌症基因组图谱（The Cancer Genome Atlas）BC队列中同样被观测到。尽管此类肿瘤的EREs可及性降低，但ER及其潜在靶基因的表达水平并未出现下降。本研究结果证实，存在一类ER表达水平未发生改变但EREs可及性降低的ER阳性BC亚群，该亚群无法通过常规的ER免疫染色进行区分。未来的研究可进一步明确此类肿瘤是否与内分泌治疗耐药相关。本研究对42例通过手术标本核心针穿刺活检获取的乳腺癌样本进行了转座酶可及性测序（Assay for Transposase-Accessible Chromatin using sequencing，ATAC-seq）分析。***请注意：由于本研究提交者已获得受试者知情同意，该同意书未预设将基因组测序数据上传至公共数据库，因此原始数据暂不提供。