Work

TRIM3 functions as a tumor suppressor and predicts prognosis in triple-negative breast cancer: a multi-omics study with clinical cohort validation

Year: 2026

Type: article

Abstract: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor prognosis and limited treatment options. Tripartite motif-containing protein 3 (TRIM3), an E3 ubiquitin ligase, has been implicated as a tumor suppressor in several cancers; however, its biological role and clinical significance in TNBC remain unclear. TRIM3 expression was analyzed using TCGA, bc-GenExMiner, CPTAC, and GEO datasets, and survival associations were evaluated with Kaplan–Meier Plotter and bc-GenExMiner. Functional assays, including CCK-8, colony formation, Transwell migration, xenograft tumorigenesis, and RNA sequencing, were performed in TRIM3-overexpressing TNBC cells. A p53-knockdown rescue experiment and immunofluorescence staining of gamma-H2A.X were also performed. Downstream pathways were explored using principal component analysis, differential expression, KEGG enrichment, EggNOG classification, gene set enrichment analysis, and protein–protein interaction networks. TNBC intrinsic molecular subtypes (BL1, BL2, M, LAR) were stratified, and the correlation between TRIM3 and immune checkpoints was analyzed. Immunohistochemistry assessed TRIM3 and TP53 expression in clinical TNBC samples, and a prognostic nomogram with a RiskScore model was constructed using Cox regression. The RiskScore model was externally validated in the METABRIC TNBC cohort. TRIM3 was significantly downregulated in TNBC compared with non-TNBC subtypes at both mRNA and protein levels. Low TRIM3 expression predicted worse survival outcomes and was strongly associated with TP53 mutation and genomic instability–related pathways. TRIM3 overexpression suppressed TNBC cell proliferation, migration, and tumor growth in vivo. Notably, TRIM3 expression was lowest in the BL1 subtype and highest in LAR, and was negatively correlated with multiple immune checkpoints. P53 knockdown reversed the tumor-suppressive effects of TRIM3 overexpression. Clinically, TRIM3 loss was more pronounced in TP53-mutated tumors. The TRIM3-based RiskScore effectively stratified patients, with high-risk individuals showing markedly poorer survival (HR = 18.42; AUC = 0.83 at 5 years and 0.90 at 10 years). The RiskScore model was further externally validated in the METABRIC cohort (HR = 1.016; 5-year AUC = 0.647). TRIM3 functions as a tumor suppressor in TNBC and is linked to TP53 mutation, genomic instability, and adverse clinical outcomes, highlighting its potential as a prognostic biomarker and therapeutic target.

Source: Scientific Reports

DOI: 10.1038/s41598-026-72591-y