Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review).

Breast cancer has the highest incidence among malignant tumors in women worldwide. Although targeted therapy, chemotherapy, and endocrine therapy have achieved significant efficacy, acquired resistance remains a major challenge affecting patient prognosis. The present review systematically outlines five core mechanisms of resistance to breast cancer treatment, including overexpression of ATP‑binding cassette transporters that reduce intracellular drug accumulation; a hypoxic and immunosuppressive tumor microenvironment, together with breast cancer stem cells, that sustains stemness and impairs treatment response; DNA methylation, histone modifications, and non‑coding RNAs that mediate epigenetic reprogramming, leading to silencing of tumor suppressors or activation of resistance pathways; compensatory activation of multiple DNA damage repair pathways, including homologous recombination, non‑homologous end joining, base excision repair, nucleotide excision repair, and mismatch repair, which compromises the efficacy of chemotherapy and poly (ADP‑ribose) polymerase inhibitors; and metabolic reprogramming involving glycolysis, amino acid, nucleotide, and lipid metabolism that supplies tumor cells with energy, reducing equivalents, and biomass for proliferation, while simultaneously promoting immune evasion. Corresponding to these mechanisms, this review also summarizes potential therapeutic strategies, including combined targeted therapy, immunotherapy, and novel drug delivery systems. Therefore, a comprehensive dissection of the multidimensional networks mediating therapy resistance in breast cancer will provide both theoretical foundations and practical pathways for discovering novel biomarkers, optimizing precision combination therapies, and ultimately prolonging patient survival.