E-cadherin involved in inactivation of WNT/β-catenin signalling in urothelial carcinoma and normal urothelial cells

Constitutive activation of WNT signalling through β-catenin, which leads to increased transcription of TCF/β-catenin target genes, is crucial in the development of many human tumour types including colorectal carcinoma and hepatoma. Its role in urothelial cancer (TCC) is unclear, since typical activating mutations are not found. We therefore determined the activity of a β-catenin/TCF-dependent promoter in proliferating normal uroepithelial cells and seven TCC cell lines, using a hepatoma line with oncogenic β-catenin as a control. Neither normal urothelial cells nor TCC lines exhibited activity under normal growth conditions. In normal cells and 5/7 TCC lines, even transfection of activated β-catenin did not restore promoter activity, suggesting repression of β-catenin/TCF activity. TCF mRNAs and total β-catenin protein levels did not differ qualitatively between inducible and noninducible cell lines, but E-cadherin expression was lacking or low in inducible TCC lines. In these, cotransfection of E-cadherin diminished activation of the TCF-dependent promoter by β-catenin. Our results make constitutive WNT/β-catenin signalling in TCC appear unlikely, thereby explaining the lack of reported mutations. However, decreased E-cadherin expression occurring in many TCC, often as a consequence of promoter hypermethylation, may confer inappropriate responsiveness to WNT factors.