MicroRNA-21 Modulates Chemosensitivity of Breast Cancer Cells to Doxorubicin by Targeting PTEN

Background and Aims. Ovexpression of microRNA-21 (miR-21) is found in various human cancers. Our aim is to investigate the association of miR-21 expression with the sensitivity of breast cancer cells to doxorubicin (ADR). Methods. The half maximal inhibitory concentration (IC50) value of ADR in resistant MCF-7/ADR or parental MCF-7 cells was determined by MTT assay. TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-21 and tumor suppressor gene (PTEN) protein. MCF-7 or MCF-7/ADR cell line was transfected with miR-21 mimic or inhibitor. The IC50 value of ADR was determined. Flow cytometry and TUNEL assays were performed to analyze apoptosis. The activity of caspase-3 was analyzed. Results. The IC50 of ADR in MCF-7 and MCF-7/ADR cells was 0.21 +/- 0.05 and 16.5 +/- 0.08 mu mol/L, respectively. We showed that upregulation of miR-21 in MCF-7/ADR cells was concurrent with downregulation of PTEN protein. MiR-21 mimic or inhibitor could obviously affect the sensitivity of breast cancer cells to ADR. Moreover, miR-21 inhibitor could enhance caspase-3-dependent apoptosis in MCF-7/ADR cells. Overexpression of PTEN could mimic the same effects of miR-21 inhibitor in MCF-7/ADR cells and PTEN-siRNA could increase the resistance of MCF-7 cells to ADR. MiR-21 inhibitor could increase PTEN protein expression and the luciferase activity of a PTEN 3' untranslated region-based reporter construct in MCF-7/ADR cells. PTEN-siRNA could partially reverse the increased chemosensitivity of MCF-7/ADR cells induced by miR-21 inhibitor. Conclusions. Dysregulation of miR-21 plays critical roles in the ADR resistance of breast cancer, at least in part via targeting PTEN. (C) 2011 IMSS. Published by Elsevier Inc.