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.
Highlights
Breast cancer is the most common malignancy and the second leading cause of cancer deaths in female [1,2,3]
We found that mouse double minute 2 (MDM2) expression correlated with epithelial-to-mesenchymal transition (EMT) markers and Snail: Snail expression was inversely associated with E-cadherin in human breast cancer samples
The results showed that MDM2 was highly expressed in two invasive breast cancer cells (MDA-MB-231 and MDA-MB-435) compared with the noninvasive breast cancer cell (MCF-7) and mammary epithelial cell (HBL-100)
Summary
Breast cancer is the most common malignancy and the second leading cause of cancer deaths in female [1,2,3]. World cancer reports have shown a continuously high breast cancer incidence in western countries and a gradually increasing trend in developing countries. Metastasis is the main cause of fatality in breast cancer patients [4]. It has been estimated that 25%–40% of patients with breast cancer will develop metastatic disease, which is generally incurable [5]. The 5-year survival rate for metastatic breast cancer patients is 20% [6]. Unraveling the molecular mechanisms underlying breast cancer metastasis is imperative
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