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Apc Gene Mutation Is Associated with a Dominant-Negative Effect upon Intestinal Cell Migration¹

The New York Hospital-Cornell University Medical Center [N. N. M., S. K. B., R. T. B., A. C., M. M. B.] and Strang Cancer Prevention Center [S. K. B., C. M., M. M. B.], New York, New York 10021

Apc-associated intestinal tumor formation appears to require functional loss of both Apc alleles. Apc has, therefore, been classified as a tumor suppressor gene. Loss of APC protein function results in increased intracellular ß-catenin, a molecule important to both cell-cell adhesion and regulation of cellular growth. In mice bearing a germ-line Apc mutation, we found that enterocyte ß-catenin expression was also increased in histologically normal intestinal mucosa. Enterocyte crypt-villus migration was decreased by 25%, and treatment of Min/+ animals with sulindac sulfide normalized both ß-catenin expression and enterocyte migration. Our data suggest that alterations in enterocyte migration occur in cells bearing a single mutant Apc allele, and that sulindac sulfide may normalize enterocyte growth in these cells.

¹ Supported by American Cancer Society Grant ACS CDA-95010-95, National Cancer Institute Grant NCI-1R29CA74162-01, and a grant from the Alice Bohmfalk Charitable Trust (all to M. M. B.) and National Institute of Health NIH Surgical Oncology Research Training Grant 525435 and a grant from the Cancer Research Foundation of America (both to N. N. M.).

² To whom requests for reprints should be addressed, at The New York Hospital-Cornell Medical Center, 525 East 68th Street, Suite F-1913, New York, NY 10021.

Received 6/ 3/97. Accepted 9/ 3/97.

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