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.
Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin
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.
Kevin G. Leong, Kyle Niessen, Iva Kulic, Afshin Raouf, Connie Eaves, Ingrid Pollet, Aly Karsan; Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin . J Exp Med 26 November 2007; 204 (12): 2935–2948. doi: https://doi.org/10.1084/jem.20071082
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