Subtype-specific sirtuin expression signatures link mitochondrial-epigenetic networks to breast cancer survival

Sirtuins (SIRT1-SIRT7) are NAD⁺-dependent regulators of mitochondrial metabolism, chromatin remodeling, and stress resilience pathways-processes that are central to both aging biology and breast cancer (BC) heterogeneity. We systematically evaluated their prognostic and transcriptional patterns across molecular subtypes of BC. We constructed an integrated BC dataset comprising gene expression and survival data containing tumors from 55 datasets. Prognostic associations with recurrence-free survival (RFS, n = 4384) were evaluated by univariate Cox and Kaplan-Meier analyses using best cutoffs with FDR control, first for individual sirtuins and then for multigene combinations. Differential expression across normal, tumor, and metastatic tissues, as well as pairwise coexpression (Spearman's ρ), was assessed using the TNMplot platform. Among individual genes, SIRT3 showed the most consistent association with improved RFS across PAM50 subtypes. Multigene signatures outperformed individual sirtuins and displayed clear subtype specificity. A three-gene panel (SIRT3+SIRT5+SIRT6) stratified risk in Luminal A (p = 8.1e-7), Luminal B (p = 6.6e-6), HER2-enriched (p = 1.0e-4), and Basal-like BC (p = 3.8e-5). In Basal-like tumors, the combination of SIRT3, SIRT6, and SIRT7 achieved the best performance (p = 2.6e-7). Top-performing panels were not simple aggregates of individually significant genes, indicating synergistic, context-dependent effects. Expression analyses revealed concordant downregulation of SIRT3 and SIRT5 in tumors, accompanied by consistent upregulation of SIRT7. Coexpression analysis revealed disease-specific rewiring: tumors exhibited a reinforced axis linking SIRT3/SIRT5/SIRT6/SIRT2, and attenuation of SIRT1 and SIRT4 coupling. Distinct integrated sirtuin scores thus capture subtype-specific metabolic/epigenetic states and provide robust RFS stratification across BC subtypes. These findings highlight sirtuins as integrators of longevity pathways and tumor metabolism, suggesting therapeutically exploitable vulnerabilities along NAD⁺-dependent regulatory axes.