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 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.
Leong
Kevin G
KG
Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Niessen
Kyle
K
Kulic
Iva
I
Raouf
Afshin
A
Eaves
Connie
C
Pollet
Ingrid
I
Karsan
Aly
A
D001665:Binding Sites; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D015820:Cadherins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C000604407:SNAI1 protein, human; D000072099:Serrate-Jagged Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors