SERPINH1 expression represents a reliable biomarker of human breast cancer aggressiveness

BACKGROUND: Extracellular matrix (ECM) remodeling is a central driver of breast cancer progression, invasion, and metastatic dissemination. Heat shock protein 47 (HSP47), encoded by SERPINH1, is a collagen-specific molecular chaperone essential for proper collagen folding and secretion, but its clinical and biological relevance in human breast cancer remains incompletely defined. METHODS: We applied an integrated multi-omics approach combining RNA sequencing, quantitative proteomics, immunohistochemistry, and spatial single-cell transcriptomics to analyze SERPINH1 expression in 21 human breast carcinomas. Internal cohort and public datasets were investigated to assess expression patterns, pathway associations, and clinical relevance across breast cancer patients. RESULTS: SERPINH1 expression strongly correlated with key ECM-remodeling genes, including COL1A1, CTGF, and DDR2, and showed robust concordance with HSP47 protein abundance. High SERPINH1 levels were tightly linked to epithelial-mesenchymal transition (EMT) programs, including ZEB1-, MMP2-, and TGF-β-driven signaling, while displaying minimal association with immune-checkpoint pathways or immune-cell infiltration. Spatial and single-cell analyses revealed enrichment of SERPINH1 in cancer-associated fibroblasts and malignant epithelial cells. Clinically, SERPINH1 expression increased from normal breast tissue to primary tumours and metastatic lesions, was highest in advanced-stage disease, and predicted reduced overall survival, particularly in luminal B breast cancer. Notably, high SERPINH1 expression was associated with improved pathological response to chemotherapy. CONCLUSIONS: These findings identify SERPINH1 as a marker of ECM-driven tumour aggressiveness and stromal reprogramming in breast cancer. By linking collagen homeostasis, EMT, and TGF-β signaling to adverse clinical outcomes, the SERPINH1-HSP47 axis emerges as a promising prognostic biomarker and a tractable therapeutic target in breast cancer.