Researchers led by Ludwig Princeton’s Yibin Kang and alumnus Zheng Sun conducted a genome-wide CRISPR knockout screen in three-dimensional (3D) tumor spheroid and two-dimensional cell culture models to identify tumor suppressors that regulate triple-negative breast cancer (TNBC), the most aggressive and treatment-resistant subtype of breast cancers. They reported in a May issue of Cancer Research that chromatin remodeling SWI/SNF complex, which directly alters DNA accessibility to regulate gene expression, emerged as a potent growth suppressor in the tumor spheroid model, which mimicked tumor growth in vivo relatively well compared to 2D cell culture. SMARCA4, the ATPase subunit of this complex, was required for the expression of the Rho GTPase factor ARHGAP29. Its loss promoted spheroid growth—generating less compact spheroids in cultures—and enhanced primary tumor growth and metastasis across several mouse models of TNBC. The researchers showed that SMARCA4 increases DNA accessibility by directly binding the promoter for ARHGAP29, enhancing its expression. SMARCA4 deletion thus depresses ARHGAP29 expression and leads to hyperactive RHOA signaling—which disrupts cell adhesion. Zheng, Yibin and colleagues also showed that SMARCA4 loss enhances growth of primary tumors and promotes metastasis in several preclinical mouse models of TNBC. The findings establish SMARCA4 and SWI/SNF as tumor suppressors of TNBC.
SMARCA4 Inhibits Breast Cancer Progression and Metastasis through RHOA Suppression
Cancer Research, 2025 May 15