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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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Breast / cytology
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Breast Neoplasms / genetics
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Cadherins / antagonists & inhibitors*
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Cadherins / genetics
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology*
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Cell Line
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Epithelial Cells / physiology*
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Female
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology*
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Jagged-1 Protein
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mesoderm / cytology
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Mesoderm / physiology*
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Receptor, Notch1 / genetics
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Receptor, Notch1 / physiology*
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Serrate-Jagged Proteins
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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Cadherins
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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NOTCH1 protein, human
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Receptor, Notch1
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SNAI1 protein, human
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Serrate-Jagged Proteins
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Snail Family Transcription Factors
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Transcription Factors