TY - JOUR T1 - Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer JF - bioRxiv DO - 10.1101/193771 SP - 193771 AU - Darren K. Patten AU - Giacomo Corleone AU - Balázs Győrffy AU - Edina Erdős AU - Alina Saiakhova AU - Kate Goddard AU - Andrea Vingiani AU - Sami Shousha AU - Lőrinc Sándor Pongor AU - Dimitri J. Hadjiminas AU - Gaia Schiavon AU - Peter Barry AU - Carlo Palmieri AU - Raul C. Coombes AU - Peter Scacheri AU - Giancarlo Pruneri AU - Luca Magnani Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/09/26/193771.abstract N2 - The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients. ER -