Subtype-resolved transcriptomic analysis reveals distinct zinc-finger regulatory hubs in breast cancer

Breast cancer comprises distinct molecular subtypes, including HER2-enriched, Luminal A, Luminal B, and triple-negative breast cancer (TNBC), each driven by distinct transcriptional programs and clinical behavior. However, the regulatory roles of zinc-finger transcription factors (ZNFs) underlying these subtype-specific programs remain incompletely defined. We performed a systematic RNA-sequencing-based comparative transcriptomic analysis across all major subtypes, incorporating differential expression analysis, pathway enrichment, protein-protein interaction network reconstruction, promoter motif scanning, and exploratory variant analysis to infer ZNF-centered regulatory architectures. HER2⁺ and Luminal B tumors exhibited the highest degree of transcriptional disruption, whereas Luminal A displayed comparatively limited deregulation. This analysis identified four subtype-specific ZNF hubs, MAZ (TNBC), ZNF596 (HER2⁺), ZNF366 (Luminal B), and ZNF671 (Luminal A), forming compact regulatory modules supported by promoter motif enrichment, indicative of putative transcription factor binding potential. Cross-subtype pathway analysis revealed conserved enrichment of Krüppel-associated box (KRAB) zinc-finger-mediated repression of endogenous retroelements, suggesting a shared epigenetic mechanism of transcriptional control. Interpretation is bounded by transcriptome-based regulatory inference without functional perturbation and by the absence of longitudinal or treatment-response data, limiting definitive causal attribution. Nonetheless, these findings establish a structured regulatory framework highlighting ZNF-driven transcriptional hierarchies across breast cancer subtypes.