Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, United States of America.
Maze Therapeutics, South San Francisco, California, United States of America.
PLoS One. 2020 Jun 25;15(6):e0235343. doi: 10.1371/journal.pone.0235343. eCollection 2020.
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 2,500 unique superenhancers 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 TGFβ pseudo-receptor BAMBI.
三阴性乳腺癌（TNBC）是一种缺乏已知分子驱动因素和有效靶向治疗的异质性疾病。细胞毒性化疗仍然是 TNBC 的主要治疗方法，与其他乳腺癌亚型相比，TNBC 的生存率明显较低。除了编码基因组内的变化外，异常增强子活性是肿瘤发生的一个公认的因素。在这里，我们使用 H3K27Ac 染色质免疫沉淀测序（ChIP-Seq）来绘制 TNBC 中活跃的顺式调控景观。我们确定了与特定增强子活性相关的不同疾病亚型，以及超过 2500 个肿瘤细胞获得但正常乳腺组织中不存在的独特超级增强子。为了确定潜在的可操作的疾病驱动因素，我们通过 CRISPR 筛选来探测与肿瘤特异性增强子相关的基因的依赖性。通过这种方式，我们确定了一些肿瘤特异性的依赖性，包括以前未被表征的对 TGFβ 假受体 BAMBI 的依赖性。
