Genetic deletions of the adenomatous polyposis coil (APC) tumor suppressor gene occur in the majority of colon cancers Loss of the APC gene products' ability to down-regulate the beta-catenin protein is hypothesized to represent a critical mechanism by which APC loss contributes to the etiology of colon cancer However, the APC protein interacts with multiple other proteins, including gamma-catenin and hDLG, that may play a role in neoplastic cell growth To date there has been little direct examination of the role of beta-catenin in the neoplastic behavior of human colon cancer cells The precise mechanisms by which beta-catenin signaling enhances the growth and survival of neoplastic cells are unknown, and the characterization of changes in gene expression resulting from beta-catenin-mediated transcriptional effects has been limited The overall goal of this project is to directly evaluate the role of beta-catenin on the neoplastic properties of APC-mutant intestinal neoplasms Antisense oligodeoxynucleotides capable of specifically suppressing beta-catenin expression in human cancer cells have been identified The ability of the antibiotic doxycycline, at clinically achievable concentrations, to inhibit beta-catenin expression has also been elucidated These beta-catenin-suppressive agents will be used to define beta-catenin-dependent effects on cell cycle and apoptotic regulatory mechanisms in APC-mutant colon cancer cells Effects of beta- catenin on c-myc expression and function will be characterized Changes in gene expression profiles of APC-mutant colon cancer cells resulting from suppression of beta-catenin expression will be evaluated, and compared with changes induced by upstream alterations in APC or downstream alterations in Tcf4 activity Effects of suppressing beta-catenin on spontaneous adenoma formation will be evaluated using APC-mutant min mice and antitumor effects resulting from the in vivo suppression of beta-catenin expression will be evaluated in APC-mutant human colon cancer xenografts Collectively, these studies will define the role of beta-catenin in the neoplastic growth of APC-mutant colon cancer cells and will characterize the efficacy of chemopreventive and therapeutic strategies that target beta-catenin in vivo.
| Foley, Paul J; Scheri, Randall P; Smolock, Christopher J et al. (2008) Targeted suppression of beta-catenin blocks intestinal adenoma formation in APC Min mice. J Gastrointest Surg 12:1452-8 |
