ELF5 modulates the estrogen receptor cistrome in breast cancer.

Catherine L Piggin,Warren Kaplan,Jason S Carroll,Alexander Swarbrick,Maria Kalyuga,Samantha R Oakes,Andrew M K Law,Susan J Clark,Christopher J Ormandy,Daniel L Roden,Matthew J Naylor,David Gallego-Ortega,Nenad Bartonicek,Mark P Molloy,Christoph Krisp,Matthew L Freedman

doi:10.1371/journal.pgen.1008531

Abstract

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 6 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.

Highlights

Estrogen receptor (ER) positive breast cancer is initially treated using endocrine therapy to withdraw estrogen, destroy its receptor, or alter ER negative (ER-)driven transcription [1]
Two thirds of breast cancers are initially treated with endocrine therapy because they are likely to rely on estrogen for their proliferation
input or total lysate (In) 2012 we hypothesised that normal developmental cell fate decisions taken by mammary progenitor cells persist in tumours that are maintained by instances of a cancerous progenitor, and that a change in the relative influence of the two major transcription factors that drive progenitor cell fate, ER to specify the hormone sensing lineage, and ELF5 to specify the ER- alveolar lineage, may allow a cancer to shift control of proliferation from estrogen to ELF5

Summary

Introduction

Estrogen receptor (ER) positive breast cancer is initially treated using endocrine therapy to withdraw estrogen, destroy its receptor, or alter ER-driven transcription [1]. Repositioning of the ER transcriptional complex can occur [8,9,10,11,12,13], altering both the expression of individual genes and transcriptional programs [9]. These events regulate the basic cell-cycle and celldeath machinery, and disruptions here can cause endocrine resistance [4]. Interventions at all of these points provide opportunities to treat endocrine-resistant disease

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Conclusion