The strength of this negative feedback regulation is demonstrated by the finding that the knockdown of β?-catenin in a pancreatic cancer line with wild-type ZNRF3 and RNF43 strongly increases the cell surface level of FZD, most likely through down-regulation of endogenous RNF43 and ZNRF3 [53]. Here, RNF43 is linked to familial pancreatic carcinoma.