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

Zhu, Yinghua, Yu, Fengyan, Jiao, Yu, Feng, Juan, Tang, Wei, Yao, Herui, Gong, Chang, Chen, Jianing, Su, Fengxi, Zhang, Yan, Song, Erwei·2011·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-11-0071

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Abstract

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. ©2011 AACR.

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Metadata

Authors
Zhu, Y., Yu, F., Jiao, Y., Feng, J., Tang, W., Yao, H., Gong, C., Chen, J., Su, F., Zhang, Y., & Song, E.
Affiliations
Authors' Affiliations: 1School of Life Sciences, Sun-Yat-Sen University, and Departments of 2Breast Surgery and 3Medical Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, People's Republic of China
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-11-14
Volume
17
Issue
22
Pages
7105-7115
ISSN
  • 1078-0432
  • 1557-3265
DOI
10.1158/1078-0432.ccr-11-0071
Cited by
221
References
1
Language
en
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