Epigenetic Reprogramming in Triple-Negative Breast Cancer: MolecularMechanisms Driving Metastasis and Therapeutic Resistance

Abstract

Triple-negative breast cancer (TNBC) represents one of the most aggressive and therapeutically challenging subtypes of breast malignancy, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Owing to its profound molecular heterogeneity, high metastatic potential, and limited targeted therapeutic options, TNBC is associated with poor clinical prognosis and elevated recurrence rates. Increasing evidence indicates that epigenetic reprogramming constitutes a fundamental driver of TNBC initiation, progression, metastatic dissemination, immune evasion, and therapeutic resistance. Aberrant DNA methylation, histone modifications, chromatin remodeling dysfunction, enhancer rewiring, and non-coding RNA dysregulation collectively reshape transcriptional landscapes that promote epithelial-to-mesenchymal transition, cancer stemness, metabolic plasticity, and tumor microenvironment remodeling. Advances in next-generation sequencing, single-cell multi-omics, and epigenomic profiling have substantially improved the understanding of dynamic epigenetic heterogeneity within TNBC tumors. Importantly, the reversible nature of epigenetic alterations has generated considerable interest in epigenetic-targeted therapies, including histone deacetylase inhibitors, bromodomain inhibitors, DNA methyltransferase inhibitors, chromatin remodeling modulators, and immunoepigenetic strategies. Emerging precision oncology approaches integrating epigenomic biomarkers and artificial intelligence-assisted molecular profiling are further transforming therapeutic stratification in TNBC. This review discusses the molecular mechanisms underlying epigenetic reprogramming in TNBC, emphasizing metastasis, therapeutic resistance, tumor microenvironment interactions, and emerging translational opportunities for precision medicine.