Major finding: Unique ER-binding site acquisition is associated with poor outcome in ER-positive tumors.
Mechanism: The plasticity of ER binding may be mediated by the pioneer factor FOXA1.
Impact: Resistance to hormone therapies is not caused by loss of ER binding to DNA.
Estrogen receptor α (ER) is overexpressed in the majority of breast cancers, but the relationship between ER-binding activity and prognosis is unclear because genome-wide binding studies have been restricted to breast cancer cell lines. Ross-Innes and colleagues performed ER chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) in a panel of primary ER-positive and ER-negative breast cancers with known outcomes and identified a core set of binding sites that were present in 75% of all ER-positive tumors regardless of outcome, indicating that ER still binds to chromatin in tumors that are resistant to hormone therapy. Interestingly, in normal human mammary glands and liver samples, relatively few ER-binding events were observed, and almost no overlap was seen between individuals, indicating that distinct genomic loci are recurrently occupied by ER in breast cancers. Differential binding analysis further identified ER-binding events that were enriched in poor-outcome tumors, and expression of the genes within 20 kilobases of these regulatory sites could predict clinical outcome of ER-positive tumors. Binding motifs for the pioneer factor FOXA1, which was highly expressed in ER-positive metastases, were enriched in the poor-outcome ER-binding events, suggesting that FOXA1 mediates changes in ER binding during cancer progression. This possibility was supported by the observation that over half of mitogen-induced changes in ER occupancy in vitro occurred at FOXA1-bound sites. Together, these findings reveal the dynamic nature of ER binding and suggest that changes in ER occupancy contribute to the aggressiveness of breast cancer.
Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 2012; 481:389–93.
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