SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breast cancer progression [ChIP-Seq]
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 proteomics and genomics approaches, we identify an oncogenic transcriptional network in TNBC involving the glucocorticoid receptor (GR), GATA6, the key oncoprotein MYC, and AP-1 transcription factors. Although these transcription factors share cis-regulatory regions, they control largely distinct oncogenic pathways. We demonstrate that SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and that inhibition of SWI/SNF-mediated chromatin remodeling decommissions the distinct enhancer repertoires and target gene programs controlled by these transcription factors. Consistently, SWI/SNF inhibition blocks cancer cell proliferation, chemoresistance, and invasion both in vitro and in vivo. Thus, we propose that several key oncogenic pathways in TNBC depend on SWI/SNF-mediated chromatin remodeling, making this disease vulnerable to SWI/SNF inhibitors. Overall design: ChIP-seq upon GR activation by DEX, siRNA KD of GATA6 , and SWI/SNF ATPase inhibition using BRM014, in BT549 triple-negative breast cancer cell line