RBM38 Regulates HORMAD1 Splicing to Enhances MEK Inhibitor Sensitivity in Breast Cancer

Abstract

Mutations in BRCA1 are key drivers of breast cancer by impairing homologous recombination. While these tumors are often sensitive to PARP inhibitors, resistance frequently emerges, highlighting the need to identify additional molecular vulnerabilities. HORMAD1 is frequently overexpressed in triple-negative breast cancer and associated with genomic instability, yet its role in therapy response in BRCA1-deficient tumors remains unclear. Here, transcriptomic profiling of BRCA1-mutant breast cancer identified HORMAD1 as one of the most upregulated and alternatively spliced genes. The splicing inhibitor Isoginkgetin globally altered alternative splicing patterns in BRCA1-mutant cells, promoting HORMAD1 exon 4 inclusion. We found that RNA-binding protein RBM38 is correlated with exon 4 inclusion, and RBM38 knockdown further sensitized BRCA1-mutant cells to MEK1 inhibition. Together, these findings define an RBM38-HORMAD1 signaling as a potential therapeutic vulnerability in BRCA1-mutant breast cancer and suggest that targeting splicing regulation may represent a promising strategy to enhance treatment efficacy.