Reduced miR-128 in Breast Tumor-Initiating Cells Induces Chemotherapeutic Resistance via Bmi-1 and ABCC5

• Published in: Clinical cancer research 2011-11, Vol.17 (22), p.7105-7115
• Main Authors: Zhu, Yinghua, Yu, Fengyan, Jiao, Yu, Feng, Juan, Tang, Wei, Yao, Herui, Gong, Chang, Chen, Jianing, Su, Fengxi, Zhang, Yan, Song, Erwei
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Culture Techniques; Cell Line, Tumor; DNA Damage - drug effects; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Targeting; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; MicroRNAs - metabolism; Multidrug Resistance-Associated Proteins - physiology; Neoplastic Stem Cells - metabolism; Nuclear Proteins - physiology; Pharmacology. Drug treatments; Polycomb Repressive Complex 1; Proto-Oncogene Proteins - physiology; Repressor Proteins - physiology; Tumors
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-0071

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. 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. 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). 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.