Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.
Darren K. Patten,
Lőrinc Sándor Pongor,
Dimitri J. Hadjiminas,
Raul C. Coombes,
Posted 26 Sep 2017
bioRxiv DOI: 10.1101/193771 (published DOI: 10.1038/s41591-018-0091-x)
Posted 26 Sep 2017
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 programs. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ER)-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 ER transcriptional activity and defines the critical subset of functional ER 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.
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