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

Journal of Experimental Medicine - Tập 204 Số 12 - Trang 2935-2948 - 2007
Kevin G. Leong1,2,3, Kyle Niessen1,2,3, Iva Kulic1,2,3, Afshin Raouf4, Connie J. Eaves4,3,5,6, Ingrid L. Pollet1,2,5, Aly Karsan1,2,3,5
11Department of Medical Biophysics,
22Department of Pathology and Laboratory Medicine, and
34Experimental Medicine Program,
43Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
55Department of Pathology and Laboratory Medicine, and
66Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

Tóm tắt

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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Thông tin xuất bản

Journal of Experimental Medicine

Tập 204 Số 12

2935-2948

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