Objective: Cd is a class 1 carcinogen that can disrupt the E-cadherin(E-cad)/b -catenin (b-cat) complex of epithelial adherence junctions (AJs). Deregulation of E-cad adhesion and changes of Wnt/b-cat signaling are known to contribute to carcinogenesis. We investigated Wnt signaling after Cd-induced E-cad disruption in cultured PTC. Methods: WKPT cells were treated with Cd (25mM, 3-9 h) to assess:1) b-cat re-distribution 2) protein-protein interaction between b-cat with a-catenin, E- cadherin and TCF4 3) reporter assays for Wnt signaling 4) Effect of overexpression of E- cadherin, TCF4 and CHOP on cell proliferation, cell proliferation and expression of Wnt responsive genes. Results: Cd reduced the interaction of b-cat with AJ components and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin-D1 and ABCB1) were upregulated by Cd, electromobility shift assays showed increased TCF4 binding to cyclin-D1 and ABCB1 promoter sequences. Overexpression of wild- type and mutant TCF4 confirmed Cd-induced Wnt signaling. Wnt signaling triggered by Cd was more prominent in proliferating subconfluent than confluent cells, which showed increased E-cad expression. Overexpression of E-cad reduced Wnt signaling, PTC proliferation and Cd toxicity. Cd also induced ROS dependent expression of the pro- apoptotic ER stress marker and Wnt suppressor CHOP which, however, did not abolish Wnt response and cell viability.Conclusion: Hence Cd may facilitate carcinogenesis of PTC by inducing the Wnt pathway by a dual mechanism to promote proliferation and survival of pre-neoplastic cells. Funded by DFG TH 345/10-1