International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

The Network of Genes Impacting Intestinal Neoplasia

W. F. Dove*, A. Bilger, R. T. Cormier, K. A. Gould, K. M. Haigis, R. B. Halberg, A. Shedlovsky, and A. R. Shoemaker
McArdle Laboratory, University of Wisconsin, Madison, Wisconsin USA

The proliferative activity of the intestinal epithelium is homeostatically regulated in normal self-renewal. While induced hyperplasia can remain homeostatically regulated, defects in the negative regulators APC or TGF can lead to neoplasia.

Our laboratory is using the power of mouse biology, genetics, and genomics to analyze the growth regulatory circuitry in the intestine. On the C57BL/6 (B6) genetic background, loss of Apc function in intestinal adenomas occurs almost exclusively by physical loss of the wild type allele of Apc (loss of heterozygosity, or LOH). We are analyzing the mechanism(s) and regulation of LOH in intestinal adenomas from B6 Min/+ mice, utilizing the Robertsonian translocation Rb(7.18)9Lub (Rb9) to generate a situation in which the Apc-linked centromere is heterozygous.

Complete substitution of the sensitive C57BL/6 background by that of AKR reduces Min tumor multiplicity by a factor of at least 50. By contrast, substitution by the BTBR/Pas background enhances tumor multiplicity at least five-fold.

One element of the suppressing effect of AKR is the Mom1 locus, containing at least two genetic factors. One of these factors is a secretory phospholipase expressed by Mom1-resistance alleles from post-mitotic Paneth and goblet cells within the tumor microenvironment. Such non-autonomous genetic factors must be discovered by the genetics of the intact mouse, not by the available methods of cell culture.

Targeted mutant alleles of candidate accessory regulatory genes have now identified effects of p53 and DNA cytosine methylase, Dnmt1. Although individual modifying genes may show only subtle quantitative effects on tumor growth rate and multiplicity, combinations of suppressive alleles can completely eliminate neoplasia. To find effective combinations of gene activities mirrors the common finding of "genetic redundancy", in which the loss of function of a single gene has no overt phenotype.


Dove, W. F., Cormier, R. T., Gould, K. A., Halberg, R. B., Merritt, A. J., Newton, M. A., and Shoemaker, A. R. The Intestinal Epithelium and Its Neoplasms: Genetic, Cellular, and Tissue Interactions. Phil. Trans. R. Soc., Lond. B., 353: 915-923, 1998.

Shoemaker, A. R., Moser, A. R., Midgley, C. A., Clipson, L., Newton, M. A., and Dove, W. F. A Resistant Genetic Background Leading to Incomplete Penetrance of Intestinal Neoplasia and Reduced Loss of Heterozygosity in ApcMin/+ Mice. Proc. Natl. Acad. Sci., U.S.A., 95: 10826-10831, 1998.

Cormier, R. T., Bilger, A., Lillich, A. J., Halberg, R. B., Hong, K. H., Gould, K. A., Borenstein, N., Lander, E. S., and Dove, W. F. The Mom1AKR Intestinal Tumor Resistance Region Consists of Pla2g2a and a Locus Distal to D4Mit64. Oncogene, 19: 3182-3192, 2000.

Halberg, R. B., Katzung, D. S., Hoff, P. D., Moser, A. R., Cole, C. E., Lubet, R. A., Donehower, L. A., Jacoby, R. F., and Dove, W. F. Tumorigenesis in the Multiple Intestinal Neoplasia Mouse: Redundancy of Negative Regulators and Specificity of Modifiers. Proc. Natl. Acad. Sci., U.S.A., 97: 3461-3466, 2000.

Cormier, R. T., and Dove, W. F. Dnmt1N/+ Reduces the Net Growth Rate and Multiplicity of Intestinal Adenomas in C57BL/6-Multiple Intestinal Neoplasia (Min)/+ Mice Independently of p53 but Demonstrates Strong Synergy with the Modifier of Min 1AKR Resistance Allele. Cancer Res., 60: 3965-3970, 2000.

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