BRCA1-mediated transcriptional repression of FABP3 - Implications for breast cancer progression and chemosensitivity

Transcriptional regulation of key target genes by BRCA1 is crucial for its diverse functions. Here, we report fatty acid-binding protein 3 (FABP3) as a novel BRCA1-repressible target gene. Functional BRCA1 represses FABP3 promoter activity while mutant BRCA1 breast cancer cell lines show higher endogenous FABP3 expression which was reduced upon introducing wild-type protein. Furthermore, using deletion constructs we identified a critical minimal responsive FABP3 promoter region and confirmed BRCA1 recruitment to this site by ChIP. FABP3 overexpression promoted proliferation, clonogenicity, and migration in breast cancer cells while conferring sensitivity to chemotherapeutic drugs. TCGA analysis correlated high FABP3/BRCA1 expression with reduced overall survival. These findings implicate FABP3 de-repression as a mechanism linking BRCA1 loss to tumor aggressiveness and chemosensitivity.