Downregulation of TNFAIP3 Associated With Poor Prognosis and Immune Response in Breast Cancer.

BACKGROUND: Breast cancer (BRCA) progression is closely linked to dysregulated inflammatory processes within the tumor microenvironment (TME). TNFAIP3, a key regulator of TNF-α signaling, plays a dual role in cancer biology, but its precise function in BRCA pathogenesis and immune modulation remains unclear. AIMS: This study aimed to elucidate the clinical significance, immune regulatory role, and molecular mechanisms of TNFAIP3 in BRCA progression. METHODS AND RESULTS: We conducted an analysis of RNA-seq data from 1113 BRCA samples and 113 normal samples sourced from TCGA, along with protein data from 125 BRCA samples and 18 normal samples obtained from the CPTAC database. Comprehensive analyses included: (1) differential expression across cancer types and BRCA subtypes; (2) correlation with clinicopathological features; (3) survival analysis using Kaplan-Meier and Cox regression; (4) immune cell infiltration assessment via ssGSEA; and (5) co-expression analysis of TNFAIP3-LINC01096. TNFAIP3 was significantly downregulated in BRCA (p < 0.001) and associated with aggressive features, including advanced TNM stage (T4 vs. T1, p = 0.021) and poor prognosis (HR = 1.48, p = 0.035). Immune profiling revealed strong correlations with cytotoxic T cells (ρ = 0.632) and dendritic cells (ρ = 0.602). A novel TNFAIP3-LINC01096 regulatory network was identified (ρ = 0.582, p < 0.001), potentially mediated by shared miR-3130-3p binding sites. CONCLUSION: Our findings suggest a role of TNFAIP3 as a critical regulator of BRCA progression and tumor immunity. The TNFAIP3-LINC01096 axis represents a promising therapeutic target, particularly for immunotherapy-resistant cases. These results provide a rationale for developing TNFAIP3-based prognostic tools and immunomodulatory strategies in BRCA management.