Exploring miRNA­target gene profiles associated with drug resistance in patients with breast cancer receiving neoadjuvant chemotherapy.

ABSTRACT

Exosomal microRNAs (miRNAs) are closely related to drug resistance in patients with breast cancer (BC); however, only a few roles of the exosomal miRNA-target gene networks have been clinically implicated in drug resistance in BC. Therefore, the present study aimed to identify the differential expression of exosomal miRNAs associated with drug resistance and their target mRNAs. In vitro microarray analysis was used to verify differentially expressed miRNAs (DEMs) in drug-resistant BC. Next, tumor-derived exosomes (TDEs) were isolated. Furthermore, it was determined whether the candidate drug-resistant miRNAs were also significant in TDEs, and then putative miRNAs in TDEs were validated in plasma samples from 35 patients with BC (20 patients with BC showing no response and 15 patients with BC showing a complete response). It was confirmed that the combination of five exosomal miRNAs, including miR-125b-5p, miR-146a-5p, miR-484, miR-1246-5p and miR-1260b, was effective for predicting therapeutic response to neoadjuvant chemotherapy, with an area under the curve value of 0.95, sensitivity of 75%, and specificity of 95%. Public datasets were analyzed to identify differentially expressed genes (DEGs) related to drug resistance and it was revealed that BAK1, NOVA1, PTGER4, RTKN2, AGO1, CAP1, and ETS1 were the target genes of exosomal miRNAs. Networks between DEMs and DEGs were highly correlated with mitosis, metabolism, drug transport, and immune responses. Consequently, these targets could be used as predictive markers and therapeutic targets for clinical applications to enhance treatment outcomes for patients with BC.