Super-enhancer acquisition drives oncogene expression in triple negative breast cancer

• Published in: PloS one Vol. 15; no. 6; p. e0235343
• Main Authors: Raisner, Ryan, Bainer, Russell, Haverty, Peter M, Benedetti, Kelli L, Gascoigne, Karen E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.06.2020; Public Library of Science (PLoS)
• Subjects: Analysis; Biology and Life Sciences; Breast cancer; Cell Line, Tumor; Chemotherapy; Chromatin; Chromatin Immunoprecipitation; CRISPR; Cytotoxicity; Dependence; Development and progression; Diagnosis; Engineering and Technology; Enhancer Elements, Genetic - genetics; Enhancers; Female; Gene Editing; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genomes; Histones - chemistry; Histones - genetics; Histones - metabolism; Humans; Immunoprecipitation; Medicine and Health Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Oncogenes; Oncogenes - genetics; RNA, Guide, CRISPR-Cas Systems - metabolism; Survival; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor cells; Tumorigenesis; Tumors; United States; United States > US; South San Francisco California; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0235343

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.