NuclearReceptors2018 Invited Speaker (1) (14 abstracts)
Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
Darren K Patten 1 , Giacomo Corleone 1 , Balázs Győrffy 2, , Edina Erdős 4 , Alina Saiakhova 5 , Kate Goddard 6 , Andrea Vingiani 7 , Sami Shousha 8 , Lőrinc Sándor Pongor 2 , Dimitri J Hadjiminas 8 , Gaia Schiavon 9 , Peter Barry 10 , Carlo Palmieri 11 , Raul C Coombes 1 , Peter Scacheri 5 , Giancarlo Pruneri 12 & Luca Magnani 1
1Department of Surgery and Cancer, The Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK; 2MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, 1117, Budapest, Hungary; 3Semmelweis University 2nd Department of Pediatrics, 1094, Budapest, Hungary; 4Department of Biochemistry and Molecular Biology, Genomic Medicine and Bioinformatic Core Facility, University of Debrecen, Debrecen 4032, Hungary; 5Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA; 6Department of Breast and General Surgery, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK; 7Department of Pathology, European Institute of Oncology, Milan, Italy; 8Centre for Pathology, Department of Medicine, Imperial, College London, Charing Cross, London, UK; 9Translational Science, IMED Oncology, AstraZeneca, Cambridge, UK; 10Department of Breast Surgery, The Royal Marsden NHS Foundation Trust, Orchard House, Downs Road, Sutton, SM2 5PT, UK; 11Institute of Translational Medicine University of Liverpool, Clatterbridge Cancer Centre, NHS Foundation Trust, and Royal Liverpool University Hospital, Liverpool, Merseyside, UK; 12Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, School of Medicine, Milan, Italy; *Equal contribution.
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 (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. In vitro work shows that TF enriched in clonal enhancers are essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. These transcription factors 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 epigenetically defined clones 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.
DOI: 10.1530/endoabs.54.IS13
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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