Estrogen receptor β role in tumour suppression of triple negative breast cancer - ChIPseq experiment. Estrogen receptor β role in tumour suppression of triple negative breast cancer - ChIPseq experiment

Breast cancer (BC) is the most common cancer in women worldwide, and is classified in multiple subtypes, including the so called triple-negative BC (TNBC). This is characterized by lack of estrogen receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), that represent common targets for BC treatment. Their absence limits the number of therapies that may be applied for TNBC treatment, suggesting the need to identify novel therapeutic targets against this disease. Several studies reported that the beta ER subtype (ERβ) is expressed in a sizeable fraction of TNBCs where its presence correlates with improved patient outcome. We evaluated ERβ expression in TNBC tissues by immunohistochemistry using two validated antibodies, demonstrating presence of this protein in 28% of samples. To investigate, in this context, the role of this estrogen receptor in TNBC biology, ERβ-expressing cell lines, representing different TNBC subtypes, were generated. Cellular and functional assays confirmed the antiproliferative activity of ERβ in TNBCs. Interaction proteomics revealed in BC nuclei the presence of several protein complexes associated with this receptor involved in chromatin remodeling, miRNA maturation and mRNA transcription. Transcriptome analyses pointed out tumor subtype-specific signaling pathways deregulation. Interestingly, among these the cholesterol biosynthesis pathway was commonly downregulated in all cell lines tested. Global analyses of ERβ binding to the genome showed its recruitment to regulatory sites of Sterol Regulatory Element-Binding Protein 1 (SREBP1), indicating a direct regulation of this pathway by the receptor. These findings suggest that drugs targeting components of cholesterol biosynthesis pathway may be new potential therapeutic options for TNBC treatment.

乳腺癌（BC）是全球女性最常见的恶性肿瘤，可分为多种亚型，其中包括所谓的三阴性乳腺癌（TNBC）。三阴性乳腺癌的特征为雌激素受体α（ERα）、孕激素受体（PR）及表皮生长因子受体2（HER2/neu）均呈阴性表达——这三者是乳腺癌治疗的经典靶点。上述靶点的缺失极大限制了三阴性乳腺癌的可选治疗方案，提示亟需针对该疾病发掘全新的治疗靶点。多项研究证实，ERβ亚型（ERβ）在相当比例的三阴性乳腺癌组织中存在表达，且其表达水平与患者预后改善显著相关。本研究采用两种经过验证的抗体，通过免疫组织化学法检测三阴性乳腺癌组织中的ERβ表达，结果显示28%的样本中可检测到该蛋白的表达。为探究该雌激素受体在三阴性乳腺癌生物学过程中的具体作用，本研究构建了表达ERβ的细胞系，该细胞系涵盖了不同的三阴性乳腺癌亚型。细胞水平与功能实验均证实，ERβ在三阴性乳腺癌中具有抗增殖活性。相互作用蛋白质组学分析发现，乳腺癌细胞核内存在多种与该受体结合的蛋白复合物，其参与染色质重塑、miRNA成熟及mRNA转录等关键生物学过程。转录组分析结果显示，肿瘤亚型特异性的信号通路出现异常调控。值得注意的是，在所检测的所有细胞系中，胆固醇生物合成通路均普遍呈现下调趋势。全基因组水平的ERβ结合分析显示，该受体可被招募至固醇调节元件结合蛋白1（SREBP1）的调控位点，表明该受体可直接调控这一通路。上述研究结果提示，靶向胆固醇生物合成通路组分的药物，或可成为三阴性乳腺癌治疗的新型潜在治疗选择。