The Journal of Experimental Medicine
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Published online November 5, 2007
doi:10.1084/jem.20071082
The Journal of Experimental Medicine, Vol. 204, No. 12, 2935-2948
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Leong et al.
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ARTICLE

 Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

Kevin G. Leong1,2,4, Kyle Niessen1,2,4, Iva Kulic1,2,4, Afshin Raouf3, Connie Eaves3,4,5,6, Ingrid Pollet1,2,5, and Aly Karsan1,2,4,5

1 Department of Medical Biophysics, 2 Department of Pathology and Laboratory Medicine, and 3 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
4 Experimental Medicine Program, 5 Department of Pathology and Laboratory Medicine, and 6 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

CORRESPONDENCE Aly Karsan: akarsan{at}bccrc.ca

Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

Abbreviations used: 5AZA, 5-azacytidine; cDNA, complementary DNA; CpG, cytosine-phosphate-guanine; EMT, epithelial-to-mesenchymal transition; HA, hemagglutinin; HDAC, histone deacetylase; MSP, methylation-specific PCR; NaBu, sodium butyrate; NotchIC, Notch intracellular domain; qPCR, quantitative RT-PCR; shRNA, short hairpin RNA; siRNA, small interfering RNA; TSA, trichostatin A; YFP, yellow fluorescent protein.

K.G. Leong, K. Niessen, and I. Kulic contributed equally to this work.


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