Journal Article

Exosomes from Drug-Resistant Breast Cancer Cells Transmit Chemoresistance by a Horizontal Transfer of MicroRNAs

Lv, Meng-meng, Liu, Xue-min, Wu, Jian-zhong, Chen, Lin, Zhong, Shan-liang, Zhao, Jian-hua, Chen, Wei-xian, Ji, Ming-hua, Tang, Jin-hai, Hu, Qing, Luo, Zhou

2014

Overview

Adriamycin and docetaxel are two agents commonly used in treatment of breast cancer, but their efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. Here we reinforced other's report that human breast cancer cell line MCF-7/S could acquire increased survival potential from its resistant variants MCF-7/Adr and MCF-7/Doc. Additionally, exosomes of the latter, A/exo and D/exo, significantly modulated the cell cycle distribution and drug-induced apoptosis with respect to S/exo. Exosomes pre-treated with RNase were unable to regulate cell cycle and apoptosis resistance, suggesting an RNA-dependent manner. Microarray and polymerase chain reaction for the miRNA expression profiles of A/exo, D/exo, and S/exo demonstrated that they loaded selective miRNA patterns. Following A/exo and D/exo transfer to recipient MCF-7/S, the same miRNAs were significantly increased in acquired cells. Target gene prediction and pathway analysis showed the involvement of miR-100, miR-222, and miR-30a in pathways implicated in cancer pathogenesis, membrane vesiculation and therapy failure. Furthermore, D/exo co-culture assays and miRNA mimics transfection experiments indicated that miR-222-rich D/exo could alter target gene expression in MCF-7/S. Our results suggest that drug-resistant breast cancer cells may spread resistance capacity to sensitive ones by releasing exosomes and that such effects could be partly attributed to the intercellular transfer of specific miRNAs.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Biological Transport / Biomarkers / Breast cancer / Cancer / Cancer cells / Cancer therapies / Cell culture / Cell cycle / Cell Cycle - drug effects / Cell Cycle - genetics / Cell Line, Tumor / Cell survival / Chemoresistance / Chemotherapy / Coculture Techniques / Communication / DNA microarrays / Doxorubicin - pharmacology / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / Exosomes / Exosomes - drug effects / Exosomes - genetics / Exosomes - metabolism / Female / Gene expression / Gene Expression Regulation, Neoplastic / Horizontal transfer / Humans / Kinases / Laboratories / MCF-7 Cells / Medicine and Health Sciences / Metabolic Networks and Pathways - genetics / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Pathogenesis / Polymerase chain reaction / Population genetics / Proteins / Ribonuclease / Ribonucleases - pharmacology / Ribonucleic acid / RNA / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Signal Transduction / Stem cells / Surgery / Target acquisition / Taxoids - pharmacology / Transfection / Tumor cells