A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions

Down-regulation of E-cadherin expression is a determinant of tumor cell inv asiveness, an event frequently associated with epithelial-mesenchymal trans itions. Here we show that the mouse E12/E47 basic helix-loop-helix transcri ption factor (the E2A gene product) acts as a repressor of E-cadherin expre ssion and triggers epithelial-mesenchymal transitions. The mouse E47 factor was isolated in a one-hybrid system designed to isolate repressors of the mouse E-cadherin promoter. Epithelial cells ectopically expressing E47 adop t a fibroblastic phenotype and acquire tumorigenic and migratory/invasive p roperties, concomitant with the suppression of E-cadherin expression. Suppr ession of E-cadherin expression under stable or inducible expression of E47 in epithelial cells occurs at the transcriptional level and is dependent o n the E-boxes of the E-cadherin promoter. Interestingly, analysis of endoge nous E2A expression in murine and human cell lines illustrated its presence in E-cadherin-deficient, invasive carcinoma cells but its absence from epi thelial cell lines. This expression pattern is consistent with that observe d in early mouse embryos, where E2A mRNA is absent from epithelia but stron gly expressed in the mesoderm. These results implicate E12/E47 as a repress or of E-cadherin expression during both development and tumor progression a nd indicate its involvement in the acquisition and/or maintenance of the me senchymal phenotype.