The APC gene is mutated in almost all colon cancers, which rank second as a cause of cancer related mortality. APC has been placed in a signaling pathway involving its regulation of beta-catenin, a protein now known to activate transcription. Abnormal accumulation of beta-catenin is observed in cancer cells mutant for APC and preliminary evidence indicates that specific mutants of beta-catenin, which exhibit abnormal protein stability, exist in other cancers. A systematic search for relevant beta-catenin mutants in a wide range of cancers will be initiated. Research efforts will focus on the elucidation of beta-catenin' potential interaction with the LEF/TCF family of transcription enhancers in cancer. Specific transcriptional enhancers associated with beta- catenin will be identified and their ability to mediate beta-catenin dependent transactivation will be tested. The effects of dominant negative mutants of the LEF/TCs on tumorigenicity will also be examined. Target genes activated by stabilized beta-catenin mutants will be determined using conditional expression and differential display methodologies. An assay employing transactivation by LEF-beta-catenin of a promotor driving luciferase expression will be developed for the purposes of high throughput screens that identify compounds having a negative effect on beta-catenin-dependent transactivation.
Deregulation of beta-catenin represents a new cancer pathway which can be exploited for the purposes of targeted therapeutic intervention. New chemotherapeutics can be identified in drug screens employing components from this pathway.
