Super-Enhancer Analysis Defines Breast Cancer Subtype And Identifies Tumor Dependencies

Epigenomic modifications define gene regulatory features that control transcription and disease cell state. Recent studies of these regulatory features have identified large clusters of enhancers, termed super-enhancers, which define key cell identity and disease genes. Using ChIP-seq and RNA-seq analysis, we have discovered Super-enhancers in breast cancer cell line models and in primary tissue and have characterized their roles in establishing tumor cell state. We find that Super-enhancers recapitulate clinical subgroups in both breast cancer cell line models and in invasive ductal carcinoma. Super-enhancer-associated genes encode known and novel therapeutic targets including kinases, phosphatases, chromatin regulators and transmembrane proteins. Such genes include key drivers such as ERRB2 in HER2+ patient samples, ESR1 in estrogen receptor positive samples, and CCND1 in samples of luminal subtype. We describe the biological and disease relevance of Super-enhancer-associated genes in the context of tumor cell state and drug target discovery. Citation Format: Matthew G Guenther, David A Orlando, Matthew L Eaton, Cindy A Collins, Mei Wei Chen, Sneha Solanki, Jakob Loven, Christian C Fritz, Eric R Olson. Super-enhancer analysis defines breast cancer subtype and identifies tumor dependencies [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-06-04.