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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Differential oestrogen receptor binding is associated with clinical outcome in breast cancer
Nature, Volume 481, No. 7381, Year 2012
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Description
Oestrogen receptor-α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes. © 2012 Macmillan Publishers Limited. All rights reserved.
Authors & Co-Authors
Teschendorff, Andrew E.
United Kingdom, London
University College London
Brown, Gordon D.A.
United Kingdom, London
Cancer Research uk
Ellis, Ian O.
United Kingdom, Nottingham
Nottingham University Hospitals Nhs Trust
Green, Andew R.
United Kingdom, Nottingham
Nottingham University Hospitals Nhs Trust
Ali, Simak M.
United Kingdom, London
Imperial College London
Chin, Suet Feung
United Kingdom, London
Cancer Research uk
Palmieri, Carlo
United Kingdom, London
Imperial College London
Caldas, Carlos
United Kingdom, London
Cancer Research uk
United Kingdom, Cambridge
University of Cambridge
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
United Kingdom, Cambridge
Cambridge Experimental Cancer Medicine Centre Ecmc
Statistics
Citations: 1,187
Authors: 8
Affiliations: 8
Identifiers
Doi:
10.1038/nature10730
ISSN:
14764687
Research Areas
Cancer
Genetics And Genomics