ELF5 modulates the estrogen receptor cistrome in breast cancer


Autoři: Catherine L. Piggin aff001;  Daniel L. Roden aff001;  Andrew M. K. Law aff001;  Mark P. Molloy aff003;  Christoph Krisp aff003;  Alexander Swarbrick aff001;  Matthew J. Naylor aff001;  Maria Kalyuga aff001;  Warren Kaplan aff001;  Samantha R. Oakes aff001;  David Gallego-Ortega aff001;  Susan J. Clark aff001;  Jason S. Carroll aff005;  Nenad Bartonicek aff001;  Christopher J. Ormandy aff001
Působiště autorů: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Victoria Street Darlinghurst Sydney, NSW, Australia aff001;  St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Australia aff002;  Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia aff003;  School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Australia aff004;  Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre Robinson Way, Cambridge, United Kingdom aff005
Vyšlo v časopise: ELF5 modulates the estrogen receptor cistrome in breast cancer. PLoS Genet 16(1): e1008531. doi:10.1371/journal.pgen.1008531
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008531

Souhrn

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 12 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance.

Klíčová slova:

Binding analysis – Breast cancer – DNA transcription – Endocrine therapy – Estrogens – Gene expression – Sequence motif analysis – Transcription factors


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