Exosomal miR-21 Derived from Paclitaxel-Resistant Breast Cancer Cells Promotes Chemoresistance in Breast Cancer via p53/PI3K/AKT/mTOR Signaling.

Abstract

Objective: To investigate whether exosomes derived from paclitaxel (PTX)-resistant breast cancer cells confer chemoresistance to parental cells and to explore the involvement of the p53/PI3K/AKT/mTOR signaling pathway in this process.

Methods: Exosomes were isolated from PTX-sensitive and PTX-resistant breast cancer cells (MCF-7 and MDA-MB-231) and characterized by transmission electron microscopy, nanoparticle tracking analysis, and detection of exosomal markers. Bioinformatics analyses were performed to predict microRNAs potentially targeting TP53. Functional assays, including Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), quantitative real-time PCR (qRT-PCR), and Western blotting, were used to assess drug sensitivity, apoptosis, and pathway-related molecular changes in recipient cells. MicroRNA inhibition and p53 overexpression approaches were applied for mechanistic validation, and key experiments were conducted in multiple breast cancer cell models.

Results: Exosomes derived from PTX-resistant cells significantly enhanced PTX resistance and attenuated apoptosis-related changes in recipient cells. Inhibition of exosomal miR-21 or restoration of p53 expression reversed these effects. Similar results were observed across different breast cancer subtypes.

Conclusion: These findings indicate that exosomal miR-21 derived from PTX-resistant breast cancer cells may contribute to chemoresistance, at least in part, by suppressing p53 and modulating PI3K/AKT/mTOR pathway activation.