The Role of Beta-catenin/Tcf Pathway Defects in Cancer

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DESCRIPTION (provided by applicant): The Wnts are a highly conserved family of secreted proteins with critical roles during development and in adult tissues, including functions in regulating cell fate determination, proliferation, cell survival, and motility. Wnts bind to cognate frizzled receptor and LDL-Receptor-Related Protein (LRP) co-receptor complexes on the cell surface and mediate intracellular signaling events through distinct pathways. The "canonical" Wnt pathway is arguably the best characterized of the Wnt-dependent pathways uncovered, and mutations in key factors in the canonical pathway have been most clearly implicated in cancer. In the canonical pathway, the beta-catenin protein is a vital effector, with certain Wnt ligands (e.g., Wnt-1) acting to stabilize beta-catenin. The glycogen synthase kinase 3beta (GSK3beta) protein functions in concert with the Axin and APC (adenomatous polyposis coli) tumor suppressor proteins and other kinases to phosphorylate (-catenin at multiple serine and threonine residues in its amino (N)-terminus. The phosphorylated beta-catenin is rapidly ubiquitinated and then degraded by the 26S proteasome. Wnt ligand binding to the Frizzled-LRP5/6 co- receptor complex leads to GSK3beta inhibition, with resultant beta-catenin stabilization. Mutational mechanisms with major roles in dysregulating beta-catenin in human cancer, include inactivation of the APC or Axin1 tumor suppressors or activating (oncogenic) mutations in beta-catenin's N-terminal phophorylation and degradation motif. Stabilization of beta-catenin via Wnts or cancer-related mutations leads to beta-catenin nuclear accumulation and its enhanced binding to T cell factor (TCF) family of transcription factors. In turn, beta-catenin/TCF complexes regulate expression of the panoply of gene products that regulate cell fate, proliferation, and other processes. Data implicating beta-catenin/TCF in the regulation of specific target genes, including key growth promoting genes, such as c-MYC and cyclin D1, have been offered. However, understanding of the role of beta- catenin/TCF pathway defects in the pathogenesis of colon and other cancers remains far from complete. Given this background, we propose the following aims: 1) To continue productive efforts to identify downstream genes whose expression is regulated by beta-catenin/TCF in colon and other cancer cells. 2) To utilize robust in vitro systems to assess the role of selected beta-catenin/TCF target genes and their protein products in the altered phenotype of colon and other cancers. 3) To continue successful efforts to assess the role of beta-catenin/TCF and selected downstream target genes in tumorigenesis, using mouse transgenic and knockout models. Our studies will highlight critical molecules contributing to the altered phenotypic traits of colon and other cancer cells. Insights into new diagnostic markers and novel therapeutic targets and approaches for cancer are also expected.