ArticleBreast cancer research : BCR2025
MAP3K1/MAP2K4 mutations drive breast cancer progression by compensating for TP53 loss through inactivation of the JNK2-p53-FOSL1 axis.
Article in Breast cancer research : BCR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
2 citing papers in PubMed.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCancer 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
methodsWe 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.
resultsMAP3K1 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.
conclusionsOur 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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.