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

Abstract

The Estrogen Receptor (ER) drives 75% of breast cancers. On activation, the ER recruits 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. Here, we present the discovery of an ER-ZMIZ1 interaction by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating that targeting ZMIZ1 results in the reduction of ER transcriptional activity at estrogen response elements and a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell-cycle genes. Integration of ENCODE data with our RNA-seq results identified ER and ZMIZ1 binding at the promoter of E2F2. We therefore propose that ER and ZMIZ1 co-regulate an important subset of cell cycle genes via a novel ER-ZMIZ1-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA, METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction ER+ patient tumours, supporting potential clinical relevance.