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

Authors

  • M.G. di Bari,

    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Laboratory of Tumor Immunology and Biology, CCR, NCI, Bethesda, Maryland 20892-1402.
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  • E. Ginsburg,

    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • J. Plant,

    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts 02114.
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  • L. Strizzi,

    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    Current affiliation:
    1. Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614-3394.
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  • D.S. Salomon,

    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • B.K. Vonderhaar

    Corresponding author
    1. Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    • Molecular and Cellular Endocrinology Section, Mammary Biology and Tumorigenesis Laboratory, Bldg 37 Room 1106A1, 37 Convent Drive, National Institutes of Health, Bethesda, MD 20892-4254.
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

  • M.G. di Bari and E. Ginsburg contributed equally to this work.

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.

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