Article

Biology of the adenomatous polyposis coli tumor suppressor.

Howard Hughes Medical Institute, Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Journal of Clinical Oncology (Impact Factor: 17.88). 06/2000; 18(9):1967-79.
Source: PubMed

ABSTRACT The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.

0 Bookmarks
 · 
91 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The proband was a 32-year-old man with sparse type of familial adenomatous polyposis with fundic gland and duodenal polyps and congenital hypertrophy of the retinal pigment epithelium without osteoma, dental abnormalities and desmoid tumors. Direct DNA sequencing did not detect germline mutations in any APC exon. However, using the multiplex ligation-dependent probe amplification method, we detected germline deletions of all APC exons. Using dual-color fluorescence in situ hybridization, we identified germline deletion of locus 5q22.1 – 22.2 that includes APC. Analysis of colorectal tumors identified somatic APC mutations in the cluster region in all polyps, but no loss of heterozygosity was detected in any polyp.
    Japanese Journal of Clinical Oncology 10/2014; 44(12):1243-1247. DOI:10.1093/jjco/hyu150 · 1.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) is an increasing burden on our society. Identifying those who are at the greatest risk and improving triage for treatment will have the greatest impact on healthcare. CRC is a prime paradigm for cancer genetics: the majority of disease results from stages of progression lending itself to prevention by early detection of the pre-disease (neoplastic) state. Approximately 10% represent well defined hereditary cancer syndromes. Hereditary CRC has the added benefit that many are slow growing and family members are armed with the knowledge of potential risk of associated carcinomas and empowerment to reduce the disease burden. This knowledge provides the indication for early endoscopic and/or surgical intervention for prevention or treatment of an entire family cohort. The molecular basis of CRC allows enhanced characterization of carcinomas, leading to targeted therapies.
    Journal of gastrointestinal oncology 10/2014; 5(5):326-335. DOI:10.3978/j.issn.2078-6891.2014.069
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.