title: Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5.
abstract: OBJECTIVE
  Tumor-initiating cells are resistant to chemotherapy, but how microRNAs play a role in regulating drug resistance of breast tumor-initiating cells (BT-IC) needs to be clarified.
  
  
  METHODS
  Lentivirus-mediated miR-128 transduction was done in BT-ICs, enriched by mammosphere cultures or CD44(+)CD24(-) fluorescence-activated cell sorting. Apoptosis and DNA damage were determined upon treatment with doxorubicin. Expression of miR-128 in breast cancer tissues was examined by in situ hybridization and correlated with breast tumor response to neoadjuvant chemotherapy and patient survival.
  
  
  RESULTS
  MiR-128 was significantly reduced in chemoresistant BT-ICs enriched from breast cancer cell lines and primary breast tumors (P < 0.01), accompanied by an overexpression of Bmi-1 and ABCC5, which were identified as targets of miR-128. Ectopic expression of miR-128 reduced the protein levels of Bmi-1 and ABCC5 in BT-ICs, along with decreased cell viability (P < 0.001) and increased apoptosis (P < 0.001) and DNA damage (P < 0.001) in the presence of doxorubicin. Reduced miR-128 expression in breast tumor tissues was associated with chemotherapeutic resistance (P < 0.001) and poor survival of breast cancer patients (P < 0.05; n = 57).
  
  
  CONCLUSIONS
  Reduction in miR-128 leading to Bmi-1 and ABCC5 overexpression is a stem cell-like feature of BT-ICs, which contributes to chemotherapeutic resistance in breast cancers. Ectopic expression of miR-128 sensitizes BT-ICs to the proapoptotic and DNA-damaging effects of doxorubicin, indicating therapeutic potential.
authors.affiliation: School of Life Sciences, Sun-Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Fengyan
authors.initials: F
authors.lastname: Yu
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Herui
authors.initials: H
authors.lastname: Yao
authors.forename: Chang
authors.initials: C
authors.lastname: Gong
authors.forename: Jianing
authors.initials: J
authors.lastname: Chen
authors.forename: Fengxi
authors.initials: F
authors.lastname: Su
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D004317:Doxorubicin; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009687:Nuclear Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C120809:ABCC5 protein, human; C069077:BMI1 protein, human; C545189:MIRN128 microRNA, human