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The B-Catenin Binding Domain of the Apc Gene Is Sufficient to Inhibit Polyp Formation
Michael V. Tirabassi, Gregory T. Banever, George M. Wadie, Maggie Lee, Richard B. Arenas, Baystate Medical Center, Springfield, MA

Background:
The Adenomatous Polyposis Coli (APC) gene is implicated in Familial Adenomatous Polyposis (FAP) syndrome, heralded by the onset of multiple polyps of the large bowel. APC is required for the degradation of B-catenin as an important step in the Wnt-1 growth pathway. The APC gene is now known to have multiple functional domains, the most important of which is the B-catenin binding domain. The purpose of this study is to determine if the B-catenin binding domain is sufficient to inhibit polyp formation in vivo.

Methods: The Min mouse, heterozygous for a truncating mutation in the murine apc gene, produces multiple polyps throughout the intestinal tract similar to FAP. Min mice (n=12) were randomly assigned to three treatment groups. Per oral treatments were performed biweekly through liposome gene delivery using one of three plasmid constructs assigned to each group: (1) Control plasmid, (2) pAPC - full length APC, (3) pBgl2 - B-catenin binding domain only.

Results:
After 4 weeks of gene therapy, intestinal polyps were counted and examined. Mean polyp numbers were decreased by 46% and 26% in the pAPC and pBgl2 groups respectively. Mean polyp sizes were unaffected by gene replacement with either pAPC and pBgl2 constructs. Both the pAPC and pBgl2 groups had a greater than 2-fold increase in intestinal epithelial apoptosis when compared to the control group.


(*Statistically significant results by Student t-test Analysis)

Conclusions:
The gene construct containing the B-catenin binding domain was sufficient to inhibit polyp formation compared to the full length APC gene construct. Despite its multi-functionality, the control of B-catenin by APC is integral for polyp formation and colorectal tumorigenesis.


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