TNBC Super-enhancers. Super-enhancer Acquisition Drives Oncogene Expression in Triple Negative Breast Cancer

Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 5000 unique enhancers acquired by tumor cells but absent from normal breast tissue. To identify potential, actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFb pseudo-receptor BAMBI. Dependency on BAMBI for tumor cell survival is predicted by the acquisition of a unique tumor-specific enhancer in a subset of TNBCs.

三阴性乳腺癌（Triple Negative Breast Cancer, TNBC）是一类具有高度异质性的疾病，目前尚未明确其公认的分子驱动因素，亦缺乏有效的靶向治疗手段。细胞毒性化疗仍是三阴性乳腺癌的主流治疗方案，但该亚型乳腺癌的生存率显著低于其他乳腺癌亚型。除编码基因组的变异外，异常增强子活性已被证实是肿瘤发生的关键诱因之一。本研究利用组蛋白H3赖氨酸27乙酰化（H3K27Ac）染色质免疫共沉淀联合测序（chromatin immunoprecipitation followed by sequencing, ChIP-Seq）技术，绘制了三阴性乳腺癌中活跃的顺式调控元件图谱。研究人员鉴定出与特定增强子活性相关的独特疾病亚型，以及肿瘤细胞获得、正常乳腺组织中缺失的5000余个独特增强子。为筛选潜在的可靶向疾病驱动因素，本研究通过CRISPR筛选（CRISPR screening）探究了与肿瘤特异性增强子关联基因的依赖性。借此鉴定出多种肿瘤特异性依赖性特征，包括此前未被阐明的转化生长因子β（transforming growth factor β, TGFβ）假受体BAMBI的依赖性。在部分三阴性乳腺癌亚型中，肿瘤细胞获得的独特肿瘤特异性增强子可预测其对BAMBI的依赖性。