title: Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells.
abstract: Recent studies have demonstrated that specific miRNAs, such as miR-221/222, may be responsible for tamoxifen resistance in breast cancer. Secreted miRNAs enclosed in exosomes can act as intercellular bio-messengers. Our objective is to investigate the role of secreted miR-221/222 in tamoxifen resistance of ER-positive breast cancer cells. Transmission electron microscopy analysis and nanoparticle tracking analysis were performed to determine the exosomes difference between MCF-7(TamR) (tamoxifen resistant) and MCF-7(wt) (tamoxifen sensitive) cells. PKH67 fluorescent labeling assay was used to detect exosomes derived from MCF-7(TamR) cells entering into MCF-7(wt) cells. The potential function of exosomes on tamoxifen resistance transmission was analyzed with cell viability, apoptosis ,and colony formation. MiRNA microarrays and qPCR were used to detect and compare the miRNAs expression levels in the two cells and exosomes. As the targets of miR-221/222, p27 and ERα were analyzed with western blot and qPCR. Compared with the MCF-7(wt) exosomes, there were significant differences in the concentration and size distribution of MCF-7(TamR) exosomes. MCF-7(wt) cells had an increased amount of exosomal RNA and proteins compared with MCF-7(TamR) cells. MCF-7(TamR) exosomes could enter into MCF-7(wt) cells, and then released miR-221/222. And the elevated miR-221/222 effectively reduced the target genes expression of P27 and ERα, which enhanced tamoxifen resistance in recipient cells. Our results are the first to show that secreted miR-221/222 serves as signaling molecules to mediate communication of tamoxifen resistance.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Wei
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Lai
authors.forename: Shentong
authors.initials: S
authors.lastname: Yu
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Ma
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huichen
authors.initials: H
authors.lastname: Li
authors.forename: Xingmei
authors.initials: X
authors.lastname: Zhu
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D055354:Exosomes / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D018809:Proliferating Cell Nuclear Antigen; D013629:Tamoxifen; C506487:ESR1 protein, human; C525709:MIR221, human; C525710:MIR222, human; C413374:p27 antigen