Background: Chemoresistance blunts the therapeutic effect of cisplatin (DDP) on Triple-Negative Breast
Cancer (TNBC). Researchers have not determined to date whether exosomes confer DDP resistance to other breast
cancer cells or whether exosomal transfer of miRNAs derived from DDP-resistant TNBC cells confer DDP resistance.
Objective: The aim of this study was to investigate the role of exosomes in chemoresistance in breast cancer.
Methods: MDA-MB-231 cells resistant to DDP (231/DDP) were established. Exosomes were isolated from 231/DDP
cells (DDP/EXO) and characterized by measuring the levels of protein markers, nanoparticle tracking analysis and
transmission electron microscopy. MDA-MB-231, MCF-7 and SKBR-3 cell lines were treated with the isolated
DDP/EXOs and cell proliferation and cytotoxicity to DDP were evaluated using MTT assays and apoptosis analyses.
Western blotting was used to examine P-glycoprotein (P-gp) expression. Additionally, a microarray was used to
analyse microRNA (miRNA) expression profiles in MDA-MB-231 and 231/DDP exosomes. The effects on miRNAs
were determined using RT-PCR. Exosomal miR-423-5p was extracted, and differential expression was verified. The
MTT cell viability assay, flow cytometry, and Transwell and immunofluorescence assays were performed to determine
if differential expression of miR-423-5p sensitized cells to DDP in vitro.
Results: Under a transmission electron microscope, the isolated exosomes exhibited a round or oval shape with a
diameter ranging between 40 and 100 nm. DDP/EXOs labelled with PKH67 were taken up by MDA-MB-231 cells.
After an incubation with DDP/EXOs, the cell lines exhibited a higher IC50 value for cisplatin, P-gp expression, migration
and invasion capabilities and a lower apoptosis rate. Furthermore, 60 miRNAs from exosomes derived from
231/DDP cells were significantly up-regulated compared to exosomes from MDA-MB-231 cells. Notably, compared
to the corresponding sensitive exosomes, miR-370-3p, miR-423-5p and miR-373 were the most differentially expressed
miRNAs in DDP-resistant exosomes. We chose miR-423-5p, and up-regulation and down-regulation of
exosomal miR-423-5p expression significantly affected DDP resistance.
Conclusions: Exosomes from DDP-resistant TNBC cells (231/DDP) altered the sensitivity of other breast cancer
cells to DDP in an exosomal miR-423-5p dependent manner. Our research helps to elucidate the mechanism of DDP
resistance in breast cancer.