Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis

Abstract

Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. In a search for key regulators of metastasis in a murine breast tumor model, we have found that the transcription factor Twist, a master regulator of embryonic morphogenesis, plays an essential role in metastasis. Suppression of Twist expression in highly metastatic mammary carcinoma cells specifically inhibits their ability to metastasize from the mammary gland to the lung. Ectopic expression of Twist results in loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT). In human breast cancers, high level of Twist expression is correlated with invasive lobular carcinoma, a highly infiltrating tumor type associated with loss of E-cadherin expression. These results establish a mechanistic link between Twist, EMT, and tumor metastasis.

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

“…Another transcriptional repressor of CDH1, SNAI2/SLUG, a downstream target of the cKIT pathway (Perez-Losada et al, 2002), is also significantly upregulated in the 'Fibroblastic' cluster, suggesting that other pathways might also be involved in EMT-related E-cadherin downregulation. For two other transcription factors that are well known to regulate Ecadherin expression in relation to EMT, TWIST (Yang et al, 2004) and SNAI1 (Cano et al, 2000), no significantly altered expression was observed in 'Fibroblastic' cells. Together, this suggests that ZFHX1B and SNAI2 are the predominant transcriptional regulators of CDH1 accounting for the EMT phenotype of breast tumour cell lines.…”

“…This process is essential for gastrulation, neural crest formation, kidney development and so on (reviewed by Thiery, 2003). Several proteins have been identified that downregulate E-cadherin expression including SNAI1/SNAIL (Batlle et al, 2000;Cano et al, 2000), ZFHX1B/SIP1 (Comijn et al, 2001), SNAI2/SLUG (Hajra et al, 2002;De Craene et al, 2005), TWIST1 (Yang et al, 2004) and DeltaEF1 (Eger et al, 2005). Altered expression of these transcription factors seems to be also associated with an altered overexpression of transcriptional repressors of E-cadherin in tumour cells (Batlle et al, 2000;Cano et al, 2000;Comijn et al, 2001;Hajra et al, 2002;Yang et al, 2004;Eger et al, 2005).…”

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…Reaction efficiency of each primer set was determined using 10-fold serial dilutions of a representative cDNA sample and expression of each gene was then normalized to GAPDH mRNA levels with efficiency correction using Relative Quantification Software (Roche Molecular Biochemicals, Laval, QC, Canada). Primer sequences for Snail and Slug are available in the RTPRimerDB database (Pattyn et al, 2006) and sequences for additional primer sets have been published earlier: IGF-IR (Jones et al, 2007) Twist (Yang et al, 2004), Zeb1 and TGF-b (Kato et al, 2007), and GAPDH (Nichols and Kirby, 2008).…”

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

“…Expression of TWIST1 has been shown to induce metastatic capacity and antiapoptotic activity of human cancer cells (Maestro et al, 1999;Yang et al, 2004). Hypoxia has been implicated in similar processes ).…”