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.
Nanjing Medical University
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All authors have declared no conflicts of interest.