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Opposite Effects of Modifiers of the Apc^Min Mutation in Intestine and Mammary Gland¹

Alina Czarnomska, Elzbieta Krysiak, Joanna Piskorowska, Miroslawa Sitarz, Kazimiera Pysniak, Tomá Pilík and Peter Demant²

Department of Genetics and Laboratory Animal Breeding, Maria Sklodowska–Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland [A. C., E. K., J. P., M. S., K. P.]; Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands [P. D.]; and Laboratory of Cellular and Molecular Immunology, Institute of Molecular Genetics, Academy of Sciences of Czech Republic, Prague, Czech Republic [T. P.]

Patterns of tumor susceptibility in different organs are widely divergent in mouse strains: one strain may be highly susceptible to tumors in one organ but resistant in another organ, whereas another strain may exhibit the opposite pattern (P. Demant, Semin. Cancer Biol., 3: 159–166, 1992). Therefore, susceptibility to tumors in different organs is assumed to be controlled by different sets of genes. On the other hand, many oncogenes and tumor suppressor genes are mutated in tumors from different organs, indicating that similar tumorigenic pathways operate in various tissues. To obtain insight into the interactions of susceptibility genes with one of such pathways, we compared tumorigenesis in intestine and mammary gland in recombinant congenic strains (RCSs) carrying the Apc^Min mutation, affecting the Wnt pathway. The presence of Apc^Min increased considerably the incidence of intestinal and mammary tumors. The individual RCSs differed in the number and latency of Apc^Min-induced intestinal and mammary tumors and histological type of the latter. Unexpectedly, the strain distribution of susceptibility to the intestinal and mammary tumors in the Apc^Min-bearing mice was opposite in the RCSs; the strains most susceptible for intestinal tumors were most resistant to mammary tumors and vice versa. This suggests that a set of genes controls the impact of the Apc^Min mutation in both organs but with opposite effects. Elucidation of the basis of the observed strain differences in organ-specific Wnt pathway-mediated tumorigenesis will help to understand the interactions between germ-line encoded allelic differences in susceptibility genes and the spectrum of somatic mutations in tumor cells.

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