Oestrogen receptor-co-factor-chromatin specificity in the transcriptional regulation of breast cancer.

Abstract

The complexity of oestrogen receptor α (ERα)-mediated transcription is becoming apparent, but global insight into the co-regulatory proteins that assist ERα transcription is incomplete. Here, we present the most comprehensive chromatin-binding landscape of ERα co-regulatory proteins to date. We map by ChIP-seq the essential p160 co-regulators (SRC1, SRC2 and SRC3), and the histone acetyl transferases p300 and CBP in MCF-7 breast cancer cells. We find a complex network of co-regulator binding, with preferential binding sites for each co-regulator. Unlike previous suggestions, we find SRC recruitment almost exclusively following ligand treatment. Interestingly, we find specific subsets of genes regulated by ligand-dependent and -independent co-regulator recruitment. Co-factor-binding profiles were integrated with expression data from cell lines and primary tumour cohorts, to reveal specific transcriptional networks that influence clinical outcome. Genes that are bound by SRC3, but not other p160 proteins, have predictive value in cohorts of breast cancer patients. By generating a robust and global view of co-factor-binding properties, we discover new levels of co-regulator complexity, but also reveal specific gene networks that may influence endocrine response.