CLIC3 emerges as a novel prognostic biomarker and therapeutic target in triple-negative breast cancer through integrated multi-omics analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) remains clinically challenging due to its aggressiveness, limited targeted therapies, and absence of reliable prognostic biomarkers. Identifying TNBC-specific molecular drivers is critical for improving patient outcomes. METHODS: We employed an integrated multi-omics approach to analyze tumor and adjacent normal tissues from 4 TNBC and 4 non-TNBC patients via RNA sequencing (RNA-seq) and whole-exome sequencing (WES), complemented by an extensive analysis of 115 TNBC and 976 non-TNBC samples from The Cancer Genome Atlas (TCGA). Prognostic screening was performed to identify potential biomarkers correlated with patient survival. In vitro experimental validation was carried out in MDA-MB-231 TNBC cells, and immunohistochemistry was used to confirm protein expression levels. RESULTS: Weighted Gene Co-expression Network Analysis (WGCNA) and comparative WES analysis revealed that TNBC exhibited unique transcriptional modules enriched in DNA replication and heterochromatin organization, distinct somatic mutation landscapes, and alternative splicing patterns. Prognostic screening identified chloride intracellular channel 3 (CLIC3) as the top risk factor for poor survival. In vitro experimental validation showed that CLIC3 knockdown significantly inhibited proliferation (CCK-8, colony formation , invasion and migration in MDA-MB-231 TNBC cells. Immunohistochemistry assay confirmed significantly higher CLIC3 protein expression in TNBC versus non-TNBC tissues. CONCLUSIONS: CLIC3 is a TNBC-specific prognostic biomarker and therapeutic target. Its inhibition impedes TNBC aggressiveness, providing a foundation for targeted therapy development.