Expression and Survival Analysis Show High Mobility Group (HMG) Family as Prognostic Biomarkers in Breast Cancer

High-mobility group (HMG) protein families are critical regulators of chromatin structure and gene expression in breast cancer. This study systematically evaluates their expression patterns, genetic interactions, and clinical relevance.

Expression profiles of HMG proteins were analyzed using mRNA data from gene expression profiling interactive analysis 2. We performed protein-level validation using the Human Protein Atlas. Prognostic significance was assessed through survival analysis, while genetic alterations were mapped using cBioPortal. Pathway enrichment and protein-protein interactions were explored with EnrichR and Search Tool for the retrieval of interacting genes/proteins, respectively. Associations with p53 mutation status were investigated using University of Alabama at Birmingham Cancer Data Analysis Portal.

HMGA1 emerged as a central driver in triple-negative breast cancer (TNBC), forming a transcriptional complex with FOXM1 that activated VEGFA-mediated angiogenesis, which correlated withwas associated with poor patient survival. In contrast, HMGA2 overexpression was paradoxically associated with favorable outcomes despite promoting tumor angiogenesis. HMGB1 regulation was linked to genomic instability and metastasis, yet it showed potential protective effects in survival analyses. HMGB2 independently predicts poor prognosis in large tumors, and HMGB3 correlates with aggressive progression. HMGB4, though expressed at low levels, is associated with improved survival in early-stage patients. HMGN1 and HMGN4 promoted tumor growth, while HMGN2 suppressed proliferation and induced apoptosis, highlighting its therapeutic potential.

HMG proteins exhibit context-dependent roles in breast cancer, with HMGA1, HMGB2-3, and HMGN1/4 driving tumors, while HMGA2, HMGB1, HMGB4, and HMGN2 show protective or paradoxical effects. These findings position HMG proteins as both biomarkers and therapeutic targets, particularly HMGA1 in TNBC angiogenesis and HMGN2 in the induction of apoptosis.