beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer

Adenomatous polyposis coli (APC) mutations are present in >70% of colon can cers. The APC protein binds to beta-catenin (beta-cat), a protein first ide ntified because of its role in E-cadherin (E-cad) cell adhesion. In some co lon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3 beta phosphorylation sites near the beta-cat NH, terminus appear to render p-cat resistant to regulation by APC and glycogen synthase kinase 3 beta, In cells with APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer fact or (Lef) transcription factors. To further explore the role of APC, beta-ca t, Tcf, and E-cad defects in gastrointestinal cancers, we assessed gastric and pancreatic cancers for constitutive Tcf transcriptional activity (CTTA) . Two of four gastric and two of eight pancreatic cancer lines showed CTTA, One gastric and one pancreatic cancer had mutations in the NH,terminal pho sphorylation sites of p-cat, The other gastric cancer with CPTA had a misse nse mutation at serine 28 of gamma-cat, a potential phosphorylation site in this beta-cat-related protein. Although E-cad is an important binding part ner for beta-cat and gamma-cat, E-cad inactivation did not result in CTTA, The beta-cat and gamma-cat mutant proteins identified in our studies strong ly activated Tcf transcription in vitro, whereas beta-cat mutant proteins w ith large NH4-terminal deletions had only modest effects on Tcf, Our result s suggest a role for Tcf deregulation in gastric and pancreatic cancer, res ulting from beta-cat and gamma-cat mutations in some cases and, in others, from yet to be defined defects. Furthermore, these data imply that the cons equences of APC and beta-cat mutations are distinct from the effects of E-c ad inactivation.