Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 22, Pages 7105-7115Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-11-0071
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Funding
- Ministry of Science and Technology of China [2010CB912800, 2011CB504203, 2009CB521706]
- Natural Science Foundation of China [30921140312, 30831160515, 30830110, 30772550, 30671930, 30972785, 30973396, 30973505, 30801376]
- Ministry of Health of China [2011ZX09102-010-02]
- Natural Science Foundation of Guangdong Province [8251008901000011, 9451008901002467]
- HuoYingdong Educational Foundation [121042]
- Science and Technology Foundation of the Guangdong Province [2009B030801005]
- Foundation of Guangzhou Science and Technology Bureau [2009Y-C011-1]
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Purpose: 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. Experimental Design: 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. Clin Cancer Res; 17(22); 7105-15. (C) 2011 AACR.
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