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

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 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.

Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology

“…For instance, in breast cancer, Notch-mediated repression of E-cadherin results in activation of β-catenin and anoikis resistance (Leong et al 2007). In cervical cancer, activated Notch1 signaling synergizes with human papillomavirus (HPV) oncogenes in the transformation of immortalized epithelial cells and generates resistance to anoikis through activation of P13K/Akt pathway (Rangarajan et al 2001).…”

Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies

“…Expression of the transcription factors Snail and Slug, which are major regulators of EMT, results in transcriptional repression of cell adhesion molecules (such as cadherins) thus allowing the cells to become more invasive [67]. Interestingly, notch signalling has been shown to regulate EMT processes in physiological and pathological events [68][69][70]. Recent evidence from the Karsan group showed that Slug was required for notchmediated repression of E-cadherin, resulting in b-catenin activation and resistance to anoikis [69].…”

“…Interestingly, notch signalling has been shown to regulate EMT processes in physiological and pathological events [68][69][70]. Recent evidence from the Karsan group showed that Slug was required for notchmediated repression of E-cadherin, resulting in b-catenin activation and resistance to anoikis [69]. This, combined with the fact that Slug was up-regulated and VE-Cadherin-2 down-regulated in cells with activated notch [25], suggests that notch signalling may in fact be actively involved in this process and thus should be investigated further to determine its precise role in vessel cell differentiation.…”

Cadherins in Cancer

“…In intestinal and mammary epithelial cells, increases in integrin-linked kinase (ILK) activity triggers Wnt signaling and transcription factors Snail and Slug, leading to downregulation of E-cadherin and induction of tumorigenic characteristics (Novak et al 1998;Oloumi et al 2004;Serrano et al 2013). Under hypoxic conditions, the Notch signaling pathway is activated and also leads to the activation of E-cadherin repressors Snail and Slug (Leong et al 2007;Sahlgren et al 2008;Niessen et al 2008). Additionally, transforming growth factor beta (TGF-β), a pivotal regulator of diverse cellular processes such as proliferation, migration, and extracellular matrix remodeling, also functions as a prominent inducer of EMT by enhancing Snail activity that subsequently leads to the loss of E-cadherin (Zeisberg et al 2003;Kalluri and Weinberg 2009).…”