Abstract
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.
Highlights
Resistance to chemotherapy remains a major obstacle in effective anticancer treatments, resulting in relapse and progression of most malignant tumors
MiR-128 was significantly reduced in chemoresistant breast tumor–initiating cells (BT-IC) enriched from breast cancer cell lines and primary breast tumors (P < 0.01), accompanied by an overexpression of Bmi-1 and ATP-binding cassette sub-family C member 5 (ABCC5), which were identified as targets of miR-128
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
Summary
Resistance to chemotherapy remains a major obstacle in effective anticancer treatments, resulting in relapse and progression of most malignant tumors. Accumulating evidence has shown that a subpopulation of cancer cells with stem cell–like features, tumor-initiating cells (T-IC), named cancer stem cells, exist in a variety of human malignancies, including hematologic [1], brain [2,3,4], breast [5, 6], prostate [7], liver [8], pancreatic [9], and colon [10, 11]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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