MAP3K1/MAP2K4 mutations drive breast cancer progression by compensating for TP53 loss through inactivation of the JNK2-p53-FOSL1 axis

作者：Sike Hu, Ailing Ji, Manxue Wang, Xia Li, Lili Sun, Ruifang Gao, Ying Zhang · 发表于：Breast Cancer Research · 年份：2025 · DOI：10.1186/s13058-025-02195-3 · 被引用次数：2 · 研究领域：Melanoma and MAPK Pathways、FOXO transcription factor regulation、Telomeres, Telomerase, and Senescence

BACKGROUND: ) subtypes, yet their functional significance and mechanistic contributions remain incompletely understood. This study aims to elucidate the role of MAP3K1/MAP2K4 mutations in BRCA pathogenesis. METHODS: We performed integrated genomic analyses using data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Functional validation was conducted in breast cancer cell lines (e.g., MCF-7, ZR-75-1) using shRNA-mediated knockdown, overexpression of dominant-negative MKK4 (MKK4DN), and western blotting. In vivo tumor growth and metastasis were assessed using a xenograft mouse model. Proteomic and phosphoproteomic data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to evaluate JNK pathway activity and FOSL1 expression across multiple cancer types. RESULTS: MAP3K1 and MAP2K4 were identified as frequently mutated in BRCA, with mutation spectra dominated by loss-of-function alterations. These mutations exhibited mutual exclusivity with TP53 alterations and were enriched in ER + tumors. Mechanistically, MAP3K1/MAP2K4 loss led to reduced JNK2 phosphorylation, impaired p53 activation at Ser15, and subsequent upregulation of FOSL1 (encoding FRA1), promoting tumor proliferation and metastasis. In vivo, MKK4DN (dominant-negative MAP2K4) expression enhanced tumor growth and lung metastasis, accompanied by decreased phospho-JNK/p53 and increased FRA1. Pan-cancer analysis revealed that MAP3K1/...