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.
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