title: Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs.
abstract: 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.
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu, China; Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Wei-xian
authors.initials: WX
authors.lastname: Chen
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu, China; Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Xue-min
authors.initials: XM
authors.lastname: Liu
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu, China; Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Meng-meng
authors.initials: MM
authors.lastname: Lv
authors.affiliation: Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China; Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Center of Clinical Laboratory, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Jian-hua
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Center of Clinical Laboratory, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Shan-liang
authors.initials: SL
authors.lastname: Zhong
authors.affiliation: Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Ming-hua
authors.initials: MH
authors.lastname: Ji
authors.affiliation: Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China; Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Hu
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu, China; Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Center of Clinical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Jian-zhong
authors.initials: JZ
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
authors.forename: Jin-hai
authors.initials: JH
authors.lastname: Tang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055354:Exosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D012260:Ribonucleases / Q000494:pharmacology; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000077143:Docetaxel; D004317:Doxorubicin; D035683:MicroRNAs; D012334:RNA, Neoplasm; D012260:Ribonucleases; D043823:Taxoids; C544266:MIRN100 microRNA, human; C525710:MIR222, human; C546086:MIRN30b microRNA, human
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