title: Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance.
abstract: A critical challenge for chemotherapy is the development of chemoresistance in breast cancer. However, the underlying mechanisms and validated predictors remain unclear. Extracellular vesicles (EVs) have gained attention as potential means for cancer cells to share intracellular contents. In adriamycin-resistant human breast cancer cells (MCF-7/ADM), we analyzed the role of transient receptor potential channel 5 (TrpC5) in EV formation and transfer as well as the diagnostic implications. Up-regulated TrpC5, accumulated in EVs, is responsible for EV formation and trapping of adriamycin (ADM) in EVs. EV-mediated intercellular transfer of TrpC5 allowed recipient cells to acquire TrpC5, consequently stimulating multidrug efflux transporter P-glycoprotein production through a Ca(2+)- and activated T-cells isoform c3-mediated mechanism and thus, conferring chemoresistance on nonresistant cells. TrpC5-containing circulating EVs were detected in nude mice bearing MCF-7/ADM tumor xenografts, and the level was lower after TrpC5-siRNA treatment. In breast cancer patients who underwent chemotherapy, TrpC5 expression in the tumor was significantly higher in patients with progressive or stable disease than in patients with a partial or complete response. TrpC5-containing circulating EVs were found in peripheral blood from patients who underwent chemotherapy but not patients without chemotherapy. Taken together, we found that TrpC5-containing circulating EVs may transfer chemoresistance property to nonchemoresistant recipient cells. It may be worthwhile to further explore the potential of using TrpC5-containing EVs as a diagnostic biomarker for chemoresistant breast cancer.
authors.affiliation: School of Pharmaceutical Sciences, Affiliated Hospital, National Engineering Laboratory for Cereal Fermentation Technology, and Wuxi Medical School, Jiangnan University, Wuxi 214122, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Dong
authors.initials: D
authors.lastname: Hua
authors.forename: Dongxu
authors.initials: D
authors.lastname: He
authors.forename: Linjun
authors.initials: L
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Junqi
authors.initials: J
authors.lastname: Wang
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Cai
authors.forename: Caiji
authors.initials: C
authors.lastname: Gao
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhang
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Hong
authors.forename: Linfang
authors.initials: L
authors.lastname: Jin
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Qi
authors.forename: Shuxian
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Gu
authors.forename: Dangtong
authors.initials: D
authors.lastname: Yang
authors.forename: Qiongxi
authors.initials: Q
authors.lastname: Pan
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Daozhen
authors.initials: D
authors.lastname: Chen
authors.forename: Liwen
authors.initials: L
authors.lastname: Jiang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050052:TRPC Cation Channels / Q000097:blood / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; D004317:Doxorubicin
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