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

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Lentivirus-mediated miR-128 transduction was done in BT-ICs, enriched by mammosphere cultures or CD44<sup>+</sup>CD24<sup>−</sup> 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 <i>in situ</i> hybridization and correlated with breast tumor response to neoadjuvant chemotherapy and patient survival.</p><p><b>Results:</b> MiR-128 was significantly reduced in chemoresistant BT-ICs enriched from breast cancer cell lines and primary breast tumors (<i>P</i> < 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 (<i>P</i> < 0.001) and increased apoptosis (<i>P</i> < 0.001) and DNA damage (<i>P</i> < 0.001) in the presence of doxorubicin. Reduced miR-128 expression in breast tumor tissues was associated with chemotherapeutic resistance (<i>P</i> < 0.001) and poor survival of breast cancer patients (<i>P</i> < 0.05; n = 57).</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 17(22); 7105–15. ©2011 AACR</i>.</p></div>