MAP3K1/MAP2K4 Mutations Drive Breast Cancer Progression by Compensating TP53 Loss via JNK2-p53-FOSL1 Axis Inactivation

Background Breast cancer (BRCA) pathogenesis involves somatic mutations in key oncogenes and tumor suppressor genes, but the full spectrum of driver mutations and their functional impact remains incompletely understood. This study aimed to identify novel BRCA-specific driver mutations and elucidate their role in tumor progression. Methods We performed integrative analysis of The Cancer Genome Atlas (TCGA) datasets to identify recurrent mutations in BRCA. Statistical analyses included mutation frequency assessment, mutual exclusivity testing, and survival correlation. Functional validation was conducted using xenograft models to evaluate tumor proliferation and metastasis. Results We identified MAP3K1 and MAP2K4 as novel BRCA-specific driver genes, mutated in 8.77% and 4.02% of cases, respectively. These mutations showed strict mutual exclusivity with TP53 alterations, indicating functional redundancy within a shared pathway. Mechanistically, MAP3K1/MAP2K4 frameshift mutations inactivated the JNK2-p53-FOSL1 axis, relieving p53-mediated suppression of the pro-metastatic factor FRA1. While TP53 mutation rates (36.4%) appeared discordantly low given BRCA aggressiveness, inclusion of MAP3K1/MAP2K4 mutations (16.6%) revealed a compensatory inactivation rate of 53.01%, aligning BRCA with other high-malignancy cancers. Functional studies demonstrated that dominant-negative MAP2K4 (MKK4DN) promoted tumor proliferation and metastasis by suppressing JNK2-mediated p53 phosphorylation and upregulating FRA1. Clinically, patients with MAP3K1/MAP2K4 frameshift mutations exhibited significantly worse overall survival. Conclusions Our findings establish MAP3K1-MAP2K4-JNK2-p53-FOSL1 as a critical tumor-suppressive axis in BRCA, where MAP3K1/MAP2K4 mutations functionally compensate for TP53 loss to drive malignancy. This study expands the genomic framework of BRCA pathogenesis and identifies potential therapeutic targets for TP53-mutant breast cancers.