Abstract
BackgroundResistance to drug therapy is a major impediment for successful treatment of patients suffering from breast cancer (BC). Tamoxifen (TAM) is an extensively used therapeutic agent, which substantially reduces the risk of recurrence and associated mortality in BC. This study demonstrated that exosomal transfer of microRNA-9-5p (miR-9-5p) enhanced the resistance of MCF-7 cells to TAM.MethodsInitially, BC-related differentially expressed genes (DEGs) and their upstream regulatory miRNAs were identified. The TAM-resistant MCF-7 (MCF-7/TAM) cell line and the non-medicated sensitive MCF-7 cell line were formulated, followed by isolation of the exosomes. Next, the apoptosis rate of exosome-treated MCF-7 cells was determined after co-culture with TAM. The interaction between miR-9-5p and ADIPOQ was identified by a combination of bioinformatic analysis and luciferase activity assay. In order to validate the effect of miR-9-5p and ADIPOQ on TAM resistance in the MCF-7 cells in vitro and in vivo, miR-9-5p was delivered into the exosomes. ADIPOQ and miR-9-5p were identified as the BC-related DEG and upstream regulatory miRNA.ResultsExosomes derived from the MCF-7/TAM cells could increase the resistance of MCF-7 cells to TAM. Notably, miR-9-5p altered the sensitivity of BC cells to TAM. In addition, ADIPOQ was negatively regulated by miR-9-5p. Furthermore, MCF-7/TAM cell-derived miR-9-5p inhibited the apoptosis of MCF-7 cells, and promoted the cell resistance to TAM. In vivo experiments in nude mice ascertained that the tumor injected with exosomal miR-9-5p showed improved resistance to TAM.ConclusionsExosomal transfer of miR-9-5p augmented the drug resistance of BC cells to TAM by down-regulating ADIPOQ, suggesting its functionality as a candidate molecular target for the management of BC.
Highlights
Resistance to drug therapy is a major impediment for successful treatment of patients suffering from breast cancer (BC)
Exosomes from MCF‐7/TAM cells can be transferred into the parental MCF‐7 cells In order to examine the influence of exosomes on the drug resistance in BC cells, the exosomes were firstly isolated from the culture supernatant of MCF-7 cells and MCF-7/TAM cells and subsequently identified
Observation of NanoSight NS300 indicated that isolated exosomes ranged from 60 to 120 nm and the concentration of exosomes in MCF-7 and MCF-7/TAM cells were 4.27 × 1012 particle/ml and 4.43 × 1012 particle/ mL, respectively (Fig. 1b)
Summary
Resistance to drug therapy is a major impediment for successful treatment of patients suffering from breast cancer (BC). This study demonstrated that exosomal transfer of microRNA-9-5p (miR9-5p) enhanced the resistance of MCF-7 cells to TAM. Extracellular vesicles, including exosomes, have been examined in regard to anti-cancer investigations as modes of provision for anti-cancer drugs, as they may reduce resistance and entail fewer adverse effects than the free drugs [9]. While exosome-delivered molecules may hasten oncogenesis, aggressiveness, and drug resistance in BC, some exosomes can transport anti-cancer drugs into BC cells, thereby minutely reducing resistance [11]. Accumulating evidence has ascertained the functionality of miRNAs as critical regulators of chief genes associated with drug resistance, and traditional therapies, in combination with miRNA-based treatment, it may be a promising option for the management of drug resistant BC [13]
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