SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breast cancer progression

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with high metastatic potential, limited treatment options and low patient survival rates. By combining functional proteomics and genomics approaches, we identify an oncogenic transcriptional network in mesenchymal and invasive TNBC involving the glucocorticoid receptor (GR), GATA6, MYC and AP-1 transcription factors. Although these transcription factors bind extensively to shared enhancers, they utilize different enhancer repertoires from this shared enhancer pool to drive distinct downstream oncogenic pathways. We demonstrate that the SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and SWI/SNF inhibition decommissions the distinct enhancer networks and pro-tumorigenic gene programs they control. Consistently, SWI/SNF inhibition blocks growth, glucocorticoid-induced chemoresistance and invasion/metastasis. Thus, we propose that SWI/SNF-mediated chromatin remodeling drives multiple hallmarks of TNBC progression, positioning SWI/SNF as a promising therapeutic target in this disease.