SWI/SNF Functions as a Gatekeeper of Enhancer Chromatin Access to Control Progression of Mesenchymal Triple-Negative Breast Cancer

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 identified 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 bound extensively to shared enhancers, they utilized different enhancer repertoires from this shared enhancer pool to drive distinct downstream oncogenic pathways. The SWI/SNF chromatin remodeling complex was a common gatekeeper of chromatin access for these transcription factors, and SWI/SNF inhibition decommissioned the distinct enhancer networks and pro-tumorigenic gene programs they control. Consistently, SWI/SNF inhibition repressed TNBC proliferation, glucocorticoid-induced chemoresistance, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Thus, these findings indicate that SWI/SNF-mediated chromatin remodeling drives TNBC progression, positioning SWI/SNF as a promising therapeutic target in this disease.