Mouse double minute 2 (MDM2) upregulates Snail expression and induces epithelial-to-mesenchymal transition in breast cancer cells in vitro and in vivo

// Xiangdong Lu 1, * , Caiyun Yan 1, * , Yi Huang 2 , Dongmin Shi 1 , Ziyi Fu 3 , Jinrong Qiu 1 , Yongmei Yin 1 1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China 2 Department of Pharmacology and Chemical Biology, Magee Women’s Research Institute, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 3 Nanjing Maternal and Child Medical Institute, Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, P. R. China * These authors have contributed equally to this work Correspondence to: Yongmei Yin, email: yongmeiyin2@126.com Keywords: breast cancer, MDM2, epithelial-mesenchymal transition, Snail Received: August 28, 2015     Accepted: April 22, 2016     Published: May 11, 2016 ABSTRACT The oncogene, mouse double minute 2 ( MDM2 ), has been implicated in the pathogenesis of numerous cancers. In this study, we investigated the role of MDM2 in epithelial-to-mesenchymal transition (EMT) and the underlying mechanisms in breast cancer cells in vitro and in vivo . The results showed that up-regulation of MDM2 in MCF-7 cells altered the cell morphology to a mesenchymal phenotype. Knockdown of MDM2 in MDA-MB-231 cells altered the cell morphology to the epithelial phenotype. In addition, overexpression of MDM2 increased the expression of N-cadherin and Vimentin and decreased the expression of E-cadherin, at both the mRNA and protein levels, in vitro and in vivo . Conversely, down-regulation of MDM2 decreased the expression of N-cadherin and Vimentin, and increased the expression of E-cadherin in vitro . Furthermore, MDM2 up-regulated both the mRNA and protein expression of Snail in vitro and in vivo . Knockdown of Snail almost abolished MDM2 induced EMT in vitro . Finally, we found that MDM2 expression correlated with EMT markers and Snail: Snail expression was inversely associated with E-cadherin in human breast cancer samples. Our findings demonstrated that MDM2 induces EMT by enhancing Snail expression in vitro and in vivo . Thus, MDM2 may be a potential target for therapy against human metastatic breast cancer.