Msx2 induces epithelial‐mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto‐1

Publisher Website
Google Scholar
Abstract
Epithelial‐mesenchymal transition (EMT) is a process occurring during both embryogenesis and early stages of invasive cancer. Epithelial cells that undergo EMT become more migratory and invasive with a mesenchymal morphology. Herein we assess EMT induction in a mouse mammary epithelial cell line driven by Msx2, a homeobox‐containing transcription factor important during mammary gland development. NMuMG cells, a normal mouse mammary epithelial cell line, stably transfected with a Msx2 cDNA showed downregulation of an epithelial marker E‐cadherin and upregulation of the mesenchymal markers vimentin and N‐cadherin. Furthermore, overexpression of Cripto‐1, a member of the epidermal growth factor‐CFC protein family already known to be involved in EMT, was detected in Msx2‐transfected cells. The expression of Cripto‐1 was accompanied by activation of the tyrosine kinase c‐Src pathway and an increase in the invasive ability of the cells. Functional assays also demonstrated inhibition of the invasive behavior of the Msx2‐transfected cells by a c‐Src specific inhibitor. Moreover, immunohistochemistry of human infiltrating breast carcinomas showed positive staining for Msx2 only in the infiltrating tumor cells while the non‐infiltrating tumor cells were negative. These results suggest that Msx2 may play a significant role in promoting EMT in epithelial cells that acquire properties involved in tumor invasion. J. Cell. Physiol. 219: 659–666, 2009. Published 2009 Wiley‐Liss, Inc.