Three microRNAs reveal breast cancer resistance patterns

A narrative review of studies indexed in PubMed, Scopus and Web of Science through December 2025 concludes that three microRNAs—miR-125b, miR-375 and miR-451—have distinct but overlapping roles in breast cancer treatment resistance. Their effects depend on disease subtype, cellular context and, for circulating miR-451, the conditions under which samples are collected. The evidence identifies candidate mechanisms and possible biomarker applications, but it does not establish that measuring or targeting any of these microRNAs is ready for clinical use.

MiR-125b appears to have a context-dependent dual role. Earlier in carcinogenesis, the review describes it mainly as a tumor suppressor, whereas therapeutic pressure can associate its activity with acquired chemoresistance. Regulation of apoptosis-related genes and pathways linked to cancer stem cell maintenance may help explain this shift. The findings indicate that the same microRNA can have opposing effects at different stages of breast cancer development, making its interpretation dependent on timing and biological setting rather than on expression alone.

The role of miR-375 is also strongly linked to breast cancer subtype. It is constitutively enriched in estrogen-receptor-positive luminal breast cancer, where reduced expression is associated with resistance to endocrine and anti-HER2 treatments. The review connects this pattern to dysregulation of the IGF1R, YAP1, JAK2/STAT3 and MTDH pathways. In triple-negative breast cancer, by contrast, miR-375 has a less clearly defined role and may participate in extracellular communication within the tumor microenvironment. The available evidence therefore supports different mechanistic interpretations across breast cancer categories rather than a single resistance model.

Lower miR-451 expression was associated in the reviewed studies with multidrug resistance involving MDR1/P-glycoprotein, Bcl-2 and YWHAZ signaling. Measurements in tissue and circulation did not necessarily move together, highlighting a possible role for extracellular vesicle trafficking in the distribution of the microRNA. The review also identifies hemolysis and other preanalytical variables as important influences on measured levels, emphasizing that laboratory procedures can affect the apparent signal. These observations nominate miR-451 as a subject for further validation but also caution against treating circulating measurements as interchangeable with tissue findings.

Collectively, the studies reviewed point to microRNAs as regulators of drug response through processes that include apoptosis, drug efflux, epithelial–mesenchymal transition, cancer stem cell maintenance and survival signaling. The three microRNAs do not form a uniform diagnostic panel: each is embedded in a different network, and their effects vary with tumor subtype, treatment pressure and sample context. Although miR-125b, miR-375 and miR-451 may eventually have value as biomarkers or therapeutic targets, the review emphasizes the need for standardized analytical methods, subtype-specific interpretation and prospective clinical validation. As a narrative synthesis rather than a new clinical trial, it maps the current evidence and identifies the gaps that remain before these potential applications can be assessed reliably.

Subject of Research: MicroRNA-mediated mechanisms of breast cancer chemoresistance

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

Article References: Ahdi, D., Rashtchi, S., Hashemi, S., Khaniani, M. S., & Derakhshan, S. M. (2026). Integrated roles of miR-125b, miR-375, and miR-451 in breast cancer chemoresistance: mechanistic insights and translational implications. Molecular Biology Reports, 53(1), Article 1510. https://doi.org/10.1007/s11033-026-12426-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12426-1

Keywords: breast cancer, chemoresistance, miR-125b, miR-375, miR-451, microRNAs, drug resistance, cancer biomarkers, cancer stem cells, tumor microenvironment, Integrated, roles