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

J Cell Physiol. 2009 Jun;219(3):659-66. doi: 10.1002/jcp.21712.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Base Sequence
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CSK Tyrosine-Protein Kinase
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Cell Line
  • DNA Primers / genetics
  • Epidermal Growth Factor / antagonists & inhibitors
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mice
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • Up-Regulation
  • src-Family Kinases

Substances

  • DNA Primers
  • Homeodomain Proteins
  • MSX2 protein
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • Tdgf1 protein, mouse
  • Epidermal Growth Factor
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human