miRNA-200c increases the sensitivity of breast cancer cells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling

Chen,Yong; Sun,Ying; Chen,Longbang; Xu,Xingxiang; Zhang,Xizhi; Wang,Buhai; Min,Lingfeng; Liu,Wei

doi:10.3892/mmr.2013.1403

miRNA-200c increases the sensitivity of breast cancer cells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling

Authors:
- Yong Chen
- Ying Sun
- Longbang Chen
- Xingxiang Xu
- Xizhi Zhang
- Buhai Wang
- Lingfeng Min
- Wei Liu
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Affiliations: Department of Medical Oncology, Subei People's Hospital, Yangzhou, Jiangsu 225000, P.R. China, Department of Pathology, Hebei United University of Basic Medical Sciences, Tangshan, Hebei 063009, P.R. China, Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China, Department of Respiratory Medicine, Subei People's Hospital, Yangzhou, Jiangsu 225000, P.R. China, Department of Medical Oncology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei 050011, P.R. China
Published online on: March 28, 2013 https://doi.org/10.3892/mmr.2013.1403
Pages: 1579-1584

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Abstract

Doxorubicin (ADR) is successfully used to treat breast cancer, however, it is often associated with the acquired resistance of breast cancer cells which eliminates the therapeutic efficiency of ADR, leading to relapse and a poorer prognosis. It has been reported that microRNA-200c (miRNA-200c), a non-coding RNA, is important in the epithelial to mesenchymal transition (EMT) and metastasis in breast cancer cells. Recent evidence demonstrated that miRNA-200c is also regulated in chemotherapeutic drug resistance, however, the precise mechanism by which this occurs remains unclear. In this study, we demonstrated that the loss of miRNA-200c correlates with the acquired resistance of breast cancer cells to ADR. In addition, the loss of miRNA-200c correlated with decreased levels of E-cadherin and PTEN, and increased levels of ZEB1 and phospho-Akt (p-Akt) in ADR-resistant breast cancer cells (MCF-7/ADR cells). More importantly, we demonstrated that the gain of miRNA-200c results in an increased sensitivity of cells to ADR, downregulation of ZEB1, upregulation of E-cadherin and PTEN, and inactivation of Akt signaling. Following the co-transfection of E-cadherin siRNA, the miRNA-200c-mediated regulation of Akt signaling and PTEN was inhibited. Results of the present study also demonstrated that Akt signaling is involved in the ADR resistance of breast cancer cells since LY294002, an inhibitor of Akt signaling, partially restored the sensitivity of MCF-7/ADR cells to ADR. In conclusion, miRNA-200c inhibited Akt signaling through its effects on E-cadherin and PTEN, resulting in the inhibition of ADR resistance in breast cancer cells.

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