Integrating single-cell and bulk RNA sequencing data establishes a cuproptosis-related gene predictive signature in breast cancer

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Abstract

Breast cancer (BRCA) remains the leading cause of cancer-related mortality in women globally. Recent studies implicate dysregulated copper homeostasis in tumorigenesis, with cuproptosis—a copper-dependent cell death mechanism—emerging as a potential therapeutic target. Here, we systematically analyzed the prognostic value of cuproptosis-related genes (CRGs) in BRCA using multi-omics data from TCGA and GEO cohorts. Weighted gene co-expression network analysis (WGCNA) identified four hub genes ( CCDC24 , TMEM65 , XPOT , NUDCD1 ) that form a prognostic signature. High-risk scores derived from this signature correlated with poor survival, distinct tumor microenvironment (TME) features, and increased TP53 mutation frequency. Functional enrichment revealed associations with immune evasion and metabolic pathways. Single-cell analysis of BRCA tissues identified diverse cell populations and differential CRG expression (CCDC24, TMEM65, XPOT, NUDCD1), linking cuproptosis to tumor metabolism, immune dynamics, and therapeutic potential. Our findings establish cuproptosis as a critical regulator of BRCA progression and propose a novel prognostic tool for clinical stratification.

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