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PMID: 17984306 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

The Journal of experimental medicine ·Vol. 204 ·No. 12 ·2007-11-26 ·Pages 2935-48

Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, Karsan A

Abstract

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 beta-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 beta-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.

MeSH Terms
Binding Sites Breast/cytology Breast Neoplasms/genetics Cadherins/antagonists & inhibitors,genetics Calcium-Binding Proteins/genetics,physiology Cell Line Epithelial Cells/physiology Female Humans Intercellular Signaling Peptides and Proteins/genetics,physiology Jagged-1 Protein Membrane Proteins/genetics,physiology Mesoderm/cytology,physiology Receptor, Notch1/genetics,physiology Serrate-Jagged Proteins Snail Family Transcription Factors Transcription Factors/genetics,physiology
Chemicals
Cadherins Calcium-Binding Proteins Intercellular Signaling Peptides and Proteins JAG1 protein, human Jagged-1 Protein Membrane Proteins NOTCH1 protein, human Receptor, Notch1 SNAI1 protein, human Serrate-Jagged Proteins Snail Family Transcription Factors Transcription Factors
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Leong Kevin G
Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Niessen Kyle
Kulic Iva
Raouf Afshin
Eaves Connie
Pollet Ingrid
Karsan Aly
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20071082
Published
2007-11-26
Epub
2007-00-05
Pages
2935-48
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118507
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20071082 PMC Full Text View journal details
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