Abstract
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 systems1,2,3. 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.
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Acknowledgements
The authors would like to thank D. Schmidt for assistance with figures, J. Hadfield for Illumina sequencing, S. MacArthur, O. Rueda, S. Vowler, R. Russell and M. Wilson for technical and bioinformatics help. We thank J. Stingl and his laboratory for help with the normal mammary gland work. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. The authors would like to thank Imperial College Healthcare NHS Trust, Human Biomaterials Resource Centre (Tissue Bank). Tumour samples from Cambridge were obtained with support from NIHR Biomedical Research Centre and the Experimental Cancer Medicine Centre. C.S.R.-I. is supported by a Commonwealth Scholarship. O.G. is part funded by a grant awarded by the Ministry of Education of the Czech Republic (Project “Oncology” MSM 0021620808) and is also a recipient of a Translational Research Fellowship from the European Society of Medical Oncology. C.P. is funded by Cancer Research UK. J.S.C. is supported by an ERC starting grant and an EMBO Young investigator award.
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C.S.R.-I., R.S., C.C. and J.S.C. designed all experiments. Experimental work was conducted by C.S.R.-I. with help from K.A.H. Computational analysis was conducted by R.S. and A.E.T., with help from M.J.D. and G.D.B. All clinical samples, clinical information and help with sample processing was provided by C.C., C.P., S.-F.C., S.A., A.R.G., I.O.E. and O.G. Histological analysis was conducted by H.R.A. The manuscript was written by C.S.R.-I., R.S., C.C. and J.S.C. with assistance from other authors.
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Ross-Innes, C., Stark, R., Teschendorff, A. et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481, 389–393 (2012). https://doi.org/10.1038/nature10730
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DOI: https://doi.org/10.1038/nature10730
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