Super-Enhancers Define Breast Cancer Subclasses And Identify Novel Tumor Cell Vulnerabilities

Breast cancer cell state is driven by genomic mutational events, aberrant signaling cascades and transcriptional misregulation. The profound clinical impact of ER-modulatory drugs underscores the importance of understanding and targeting the transcriptional dependencies of breast cancer cells in an effort to create new therapeutics. Recently, large clusters of cis-acting enhancers, termed Super-enhancers, have emerged as dominant transcriptional regulators of oncogenes and other key tumor drivers in cancer cells, indicating that these elements control and maintain breast tumor cell state. Mapping these elements and the genes they control in patient tumors can provide insight into breast cancer classification and identify therapeutic targets. We have discovered Super-enhancers in breast cancer patient tissue and have characterized their roles in enforcing tumor cell state. We find that Super-enhancers define known clinical subgroups in invasive ductal carcinoma and pinpoint the putative transcriptional drivers of each subgroup. Super-enhancer-associated genes encode both known and novel therapeutic targets including kinases, phosphatases, chromatin regulators and transmembrane proteins, including key drivers such as ERRB2 in HER2+ patient samples, ESR1 in estrogen receptor positive samples, and CCND1 in samples of luminal subtype. shRNA knockdown confirms that Super-enhancer regulated genes are indeed essential for tumor cell survival and that Super-enhancer analysis in primary patient samples can be used to define new subtype specific cancer vulnerabilities. In sum, we describe the biological and disease relevance of Super-enhancer-associated genes in the context of tumor cell state, genome mutational landscape and drug target discovery. Citation Format: Cindy Collins, Mei Wei Chen, Matthew Eaton, David Orlando, Michael McKeown, Christian Fritz, Eric Olson, Matthew Guenther. Super-enhancers define breast cancer subclasses and identify novel tumor cell vulnerabilities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3837. doi:10.1158/1538-7445.AM2015-3837