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Background <p>Cancer progression is driven by somatic mutations, with alterations in driver genes such as tumor suppressors and oncogenes playing critical roles. In breast cancer (BRCA), mutations in MAP3K1 and MAP2K4 are recurrent, especially in estrogen receptor-positive (ER<sup>+</sup>) 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.</p> Methods <p>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.</p> Results <p>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/MAP2K4 mutations compensate for TP53 loss in regulating FOSL1 expression, particularly in tumors with moderate TP53 mutation rates.</p> Conclusions <p>Our findings establish MAP3K1 and MAP2K4 as key tumor suppressors in BRCA that operate via the JNK2–p53–FOSL1 axis. Their inactivation provides an alternative mechanism for p53 pathway disruption, adhering to the “minimal necessary alteration” principle in cancer signaling. This study highlights the dual regulatory mechanisms controlling FRA1 expression and offers insights into breast cancer heterogeneity, with potential implications for targeted therapy and patient stratification.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月16日

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  • Sike Hu,
  • Ailing Ji,
  • Manxue Wang,
  • Xia Li,
  • Lili Sun,
  • Ruifang Gao,
  • Ying Zhang

摘要

Background

Cancer progression is driven by somatic mutations, with alterations in driver genes such as tumor suppressors and oncogenes playing critical roles. In breast cancer (BRCA), mutations in MAP3K1 and MAP2K4 are recurrent, especially in estrogen receptor-positive (ER+) 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/MAP2K4 mutations compensate for TP53 loss in regulating FOSL1 expression, particularly in tumors with moderate TP53 mutation rates.

Conclusions

Our findings establish MAP3K1 and MAP2K4 as key tumor suppressors in BRCA that operate via the JNK2–p53–FOSL1 axis. Their inactivation provides an alternative mechanism for p53 pathway disruption, adhering to the “minimal necessary alteration” principle in cancer signaling. This study highlights the dual regulatory mechanisms controlling FRA1 expression and offers insights into breast cancer heterogeneity, with potential implications for targeted therapy and patient stratification.