Integrated roles of miR-125b, miR-375, and miR-451 in breast cancer chemoresistance: mechanistic insights and translational implications.

Breast cancer is the most frequently diagnosed malignancy among women globally and the resistance to chemotherapy and targeted therapies remains a major hindrance to successful treatment. Emerging data suggests that microRNAs (miRNAs) play a critical role in controlling drug response by modulating cellular processes such as apoptosis, drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) maintenance and survival signaling pathways. This narrative review aims to summaries the existing data about the involvement of three important miRNAs, miR-125b, miR-375 and miR-451 in breast cancer chemoresistance, based on the studies gathered from PubMed, Scopus and Web of Science up to December 2025. Current data indicates that miR-125b has a context-dependent dual role, mainly operating as a tumor suppressor during early carcinogenesis, but contributing to acquired chemoresistance under therapeutic pressure via regulating apoptosis-related genes and CSC-associated pathways. In contrast, the biological roles of miR-375 and miR-451 are highly dependent on breast cancer subtype. miR-375 is constitutively enriched in ER-positive luminal breast cancer, where its downregulation contributes to endocrine and anti-HER2 therapy resistance via dysregulation of the IGF1R, YAP1, JAK2/STAT3 and MTDH pathways, whereas its role in triple-negative breast cancer remains incompletely understood and may involve extracellular communication within the tumor microenvironment. Similarly, lower miR-451 expression induces MDR1/P-glycoprotein, Bcl-2 and YWHAZ signaling-mediated multidrug resistance, with differences in tissue and circulation levels underscoring the relevance of extracellular vesicle trafficking and preanalytical variables including hemolysis. These data collectively suggest the potential value of these miRNAs as biomarkers and therapeutic targets but also highlight the need for subtype-specific interpretation, standardized analytical methods, and further prospective clinical validation before clinical implementation.