To date, although many significant advances have been made in chemotherapy, chemo-resistance still remains a major obstacle to successful treatment of breast cancer. For poor understanding of the mechanisms underlying chemo-resistance, it is necessary to identify the possible biomarkers and pathways in breast cancer resistant to chemotherapy. On the basis of our previous finding that drug-sensitive breast cancer cells could partly increased their resistance capacity by the uptake of drug-resistant cell-derived exosomes, which contain some higher levels of miRNAs (miR-100, miR-222, and miR-30a).
To identify the mechanism of exosome-mediated drugresistance, we compared the characteristics of exosomes derived from MCF/7-ADR and MCF/7-S cell lines.
A marked increase in the exosome release was observed in ADR-resistant cells compared with sensitive cells. Then, we confirmed that exosomes from MCF/7-ADR cells confer drug-resistance to sensitive cells, with the modulation of the miR-222 level. To exclude effects of other relevant factors on resistance, we chose exosomes produced by HBL-100 cells as a suitable carrier for loading miR-222 mimic (or inhibitor), which was achieved by electroporation. The electroporation conditions were optimized in terms of the voltage and exosome concentration. Importantly, we further examined the influence of miR-222 inhibitor-containing exosomes (inhibitor-exos) on the pathways downstream of miR-222 and the potential therapeutic effects both in vitro and in vivo. Mice bearing MCF-7/ADR xenograft tumors that were injected with inhibitor-exos showed greatly suppressedtumor growth, along with a lower miR-222 level and higher PTEN expression. Similar results for the miR-222 and PTEN levels were observed in serum exosomes from the mice injected with inhibitor-exos compared with the control mice. More importantly, for the first time, we detected the levels of miR-222 and its target gene, PTEN, along with the exosomal marker TSG101, in breast cancer patients who received anthracycline/taxane-based chemotherapy to explore the potential clinical implications of miR-222-containing exosomes in chemotherapy.
These findings demonstrate that miR-222-containing exosomes transmit drugresistance by modulating the miR-222 pathway; furthermore, miR-222-containing exosomes may be a promising biomarker for predicting the efficiency and outcome of chemotherapy in breast cancer patients.
Clinical trial identification
Legal entity responsible for the study
Nanjing Medical University
All authors have declared no conflicts of interest.