Differential oestrogen receptor binding is associated with clinical outcome in breast cancer

Abstract

SummaryOestrogen 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 systems1-3. We now 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 outcome and in distant ER positive (ER+) metastases. We find that drug resistant cancers still have ER-chromatin occupancy, 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, poor outcome ER regulatory regions observed in primary tumours reveal gene signatures that predict clinical outcome in ER+ 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 time scale. The parallel redistribution of ER and FoxA1 cis-regulatory elements 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.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Fullwood et al [24] mapped the chromatin interaction network bound to ERα in the human genome by utilizing chromatin interaction analysis by paired end-tag sequencing and discovered that most high-confidence ERα-binding sites are anchored to gene promoters through long-range chromatin interactions like looping. Similar three-dimensional chromatin interaction studies using tissue samples from cancer patients reveal that the clinical outcome of breast cancers is decided at the level of chromatin interaction by ERα [25]. Furthermore, these studies also demonstrate that drug-resistant breast cancers still recruit ERα to the chromatin but with different binding affinities.…”

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

“…Ross-Innes et al also explored ER binding sites in primary breast cancer using ChIP-seq analysis and identified differential ER-binding profiles that are correlated with good or poor clinical outcomes, suggesting that ChIP-seq analysis will be useful for providing predictive prognoses in breast cancer [82] .…”

A patient‐derived explant (PDE) model of hormone‐dependent cancer

“…Estradiol (E2)‐activated ERα binds to cis ‐regulatory elements of target genes such as the PGR (Ross‐Innes et al ., 2012). Candidate gene analyses performed on RNA extracted from ERα‐positive PDEs ( n  = 14) cultured for 24 h with E2 revealed a range of responses to hormone treatment.…”

“…Breast cancer PDEs cultured in complete medium containing vehicle (EtOH; 0.1%), 17β‐estradiol (E2; 10 n m ), or synthetic PGR agonist R5020 (10 n m ) for 72 h were harvested, crosslinked, and processed for ChIP‐seq analysis as described previously (Ross‐Innes et al ., 2012). The estrogen receptor alpha (ERα) HC‐20 antibody (Santa Cruz Biotechnologies, Dallas, TX, USA) was used for immunoprecipitation of ERα from PDE tissue lysates.…”