DNA Methyltransferase Inhibitors in Triple-Negative Breast Cancer: Mechanisms, Limitations, and Therapeutic Potential

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype that lacks estrogen receptor (ER), progesterone receptor (PR), and HER2 amplification. Its aggressiveness, restricted therapeutic targets, and early susceptibility to metastasize make it a major clinical challenge. Accumulating evidence suggests the critical role of DNA methylation, in TNBC progression, immune evasion, and resistance to conventional therapies. DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) which modifies DNA methylation, tend to be overexpressed in TNBC and regulate gene silencing programs that affect tumor suppressor genes, hormone receptor expression (e.g., ESR1 and PGR), cell adhesion molecules, and DNA damage response pathways.This review incorporates findings from recent genomic and epigenomic studies to provide insights into the mechanisms by which DNMT-mediated methylation profiles contribute to TNBC biology and therapy resistance. In addition, it addresses the therapeutic landscape of DNMT inhibitors (DNMTis). Preclinical studies reveal that DNMTis have the potential to repair aberrant methylation, restore hormone receptor expression, make TNBC cells chemosensitive and immunological checkpoint blockable, and suppress cancer stem cell populations. Nevertheless, their clinical usage is still limited by drawbacks such as inadequate pharmacokinetic properties, off-target toxicity, and the unavailability of powerful epigenetic biomarkers to stratify patients.In light of these limitations, the potential future of epigenetic therapy in TNBC would be rational combination strategies, biomarker-based patient screening, and mechanism-driven drug design. Understanding the nature of DNA methylation not only offers with it new promises for intervention but also valuable information regarding the molecular basis of this problematic disease subset.