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ß- and -Catenin Mutations, but not E-Cadherin Inactivation, Underlie T-Cell Factor/Lymphoid Enhancer Factor Transcriptional Deregulation in Gastric and Pancreatic Cancer¹

Departments of Internal Medicine [K. C., F. T. K., X. J., M. H., J-m. Q., E. R. F.], Surgery [A. Y.], Human Genetics [E. R. F.], and Pathology [E. R. F.], The Cancer Center and the Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109; and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510 [D. L. R., J. C.]

Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers. The APC protein binds to ß-catenin (ß-cat), a protein first identified because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3ß phosphorylation sites near the ß-cat NH₂ terminus appear to render ß-cat resistant to regulation by APC and glycogen synthase kinase 3ß. In cells with APC or ß-cat defects, ß-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription factors. To further explore the role of APC, ß-cat, 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 NH₂-terminal phosphorylation sites of ß-cat. The other gastric cancer with CTTA had a missense mutation at serine 28 of -cat, a potential phosphorylation site in this ß-cat-related protein. Although E-cad is an important binding partner for ß-cat and -cat, E-cad inactivation did not result in CTTA. The ß-cat and -cat mutant proteins identified in our studies strongly activated Tcf transcription in vitro, whereas ß-cat mutant proteins with large NH₂-terminal deletions had only modest effects on Tcf. Our results suggest a role for Tcf deregulation in gastric and pancreatic cancer, resulting from ß-cat and -cat mutations in some cases and, in others, from yet to be defined defects. Furthermore, these data imply that the consequences of APC and ß-cat mutations are distinct from the effects of E-cad inactivation.

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