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

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(1-3). 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.