A mouse mutation, Multiple intestinal neoplasia (Min), predisposes to intestinal adenomas in animals carrying one copy of the mutant gene. Min is a nonsense mutation in the murine homolog of the human APC (adenomatous polyposis coli) locus. The Min locus thus has the character of a tumor suppressor element. The number of intestinal tumors that form can be modified by genetic background. We propose: (1) To determine whether allele loss at the Min or mMCC loci contributes to tumor formation or progression. (2) To determine whether the developmental stage of the intestine affects susceptibility to tumor initiation. (3) To investigate the pattern of Min gene expression in the developing and mature intestine and mammary gland of the mouse. (4) To determine whether tumor formation is a function of the Min genotype of the intestinal stem cell. (5) To determine the number, chromosomal location, and molecular identity of the major resistant modifier alleles carried by two tumor-resistant mouse strains. The Min locus seems to be an essential development element. Thus, we also propose: (6) To characterize the lethal phenotype of the mutant homozygotes and the expression of the Min gene during embryogenesis. By good fortune, we have come upon a mouse mutant for familiar intestinal cancer that is a precise molecular replica of the common human disease. This mouse mutant permits experimental investigation of the role of the gene of interest in intestinal development and neoplasia, and also in other tissues of the embryo, the neonate, and the adult. We hope that a deep understanding will emerge of neoplasia in a self-renewing tissue, its relationship to normal development, and the possibilities for intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050585-06
Application #
2093855
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1989-07-17
Project End
1997-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Cormier, R T; Bilger, A; Lillich, A J et al. (2000) The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19:3182-92
Cormier, R T; Dove, W F (2000) 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 1(AKR) resistance allele. Cancer Res 60:3965-70
Gould, K A; Dove, W F (1998) Analysis of the Mom1 modifier of intestinal neoplasia in mice. Exp Lung Res 24:437-53
Shoemaker, A R; Moser, A R; Midgley, C A et al. (1998) 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 95:10826-31
Shoemaker, A R; Luongo, C; Moser, A R et al. (1997) Somatic mutational mechanisms involved in intestinal tumor formation in Min mice. Cancer Res 57:1999-2006
Cormier, R T; Hong, K H; Halberg, R B et al. (1997) Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet 17:88-91
Dove, W F; Clipson, L; Gould, K A et al. (1997) Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res 57:812-4
Shoemaker, A R; Gould, K A; Luongo, C et al. (1997) Studies of neoplasia in the Min mouse. Biochim Biophys Acta 1332:F25-48
Merritt, A J; Gould, K A; Dove, W F (1997) Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages. Proc Natl Acad Sci U S A 94:13927-31
Bilger, A; Shoemaker, A R; Gould, K A et al. (1996) Manipulation of the mouse germline in the study of Min-induced neoplasia. Semin Cancer Biol 7:249-60

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