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

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 þ CD24 À 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. Ó2011 AACR.

MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia

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miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

“…Some miRNAs are indicators of drug resistance and confer resistance to a variety of chemotherapeutic drugs [9,10,11]. MiR-218 is expressed in several carcinomas and plays critical roles in carcinogenesis, cancer proliferation and cancer metastasis.…”

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

“…The regulatory mechanism of miR‐128‐3p seems to be relevant also in breast cancer patients as our analysis suggests that miR‐128‐3p is lower expressed in nonluminal breast cancer compared to luminal‐like subtypes. Low‐level expression of miR‐128‐3p also correlates with poor clinical outcome of patients with breast cancer (Qian et al ., 2012; Zhu et al ., 2011). Other studies have shown that miR‐128‐3p is also lower expressed in other tumor tissues and that its overexpression inhibits tumor cell proliferation, angiogenesis, and invasion (Evangelisti et al ., 2009; Hu et al ., 2014; Palumbo et al ., 2013).…”

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