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

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...

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Autores principales: Leong, Kevin G., Niessen, Kyle, Kulic, Iva, Raouf, Afshin, Eaves, Connie, Pollet, Ingrid, Karsan, Aly
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118507/
https://www.ncbi.nlm.nih.gov/pubmed/17984306
http://dx.doi.org/10.1084/jem.20071082
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author Leong, Kevin G.
Niessen, Kyle
Kulic, Iva
Raouf, Afshin
Eaves, Connie
Pollet, Ingrid
Karsan, Aly
author_facet Leong, Kevin G.
Niessen, Kyle
Kulic, Iva
Raouf, Afshin
Eaves, Connie
Pollet, Ingrid
Karsan, Aly
author_sort Leong, Kevin G.
collection PubMed
description 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.
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spelling pubmed-21185072008-05-26 Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin Leong, Kevin G. Niessen, Kyle Kulic, Iva Raouf, Afshin Eaves, Connie Pollet, Ingrid Karsan, Aly J Exp Med Articles 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. The Rockefeller University Press 2007-11-26 /pmc/articles/PMC2118507/ /pubmed/17984306 http://dx.doi.org/10.1084/jem.20071082 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Articles
Leong, Kevin G.
Niessen, Kyle
Kulic, Iva
Raouf, Afshin
Eaves, Connie
Pollet, Ingrid
Karsan, Aly
Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title_full Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title_fullStr Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title_full_unstemmed Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title_short Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
title_sort jagged1-mediated notch activation induces epithelial-to-mesenchymal transition through slug-induced repression of e-cadherin
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118507/
https://www.ncbi.nlm.nih.gov/pubmed/17984306
http://dx.doi.org/10.1084/jem.20071082
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