ZMIZ1—A novel Estrogen Receptor co activator that enhances the growth of ER+ breast cancer

The Estrogen Receptor (ER) drives 75% of breast cancers. On activation, the ER recruits specific co-factors to form a transcriptionally active complex. These co-factors can modulate tumour growth and understanding their roles can help to identify new therapeutic targets. We applied a quantitative proteomics method, qPLEX-RIME , to analyse the ER protein complex and characterise changes in protein-protein interactions on activation. Our analysis identified ZMIZ1 as novel co-factor within the ER chromatin-bound complex, extending its known role as a co-factor of the Androgen Receptor. We find further evidence for an ER-ZMIZ1 interaction by showing that both proteins are co-expressed in biopsy samples. We characterise ZMIZ1 function by showing that targeting ZMIZ1 results in the reduction of ER transcriptional activity and significantly reduces the proliferation of ER-positive cell lines. We validated these results genome-wide by RNA-seq and identified that targeting ZMIZ1 resulted in a specific reduction of estradiol-induced cell cycle genes. These results establish ZMIZ1 as a having a key role in the ability of the ER to activate key genes that drive the proliferation of breast cancer, and its biological importance in patient tumours.