[CANCER RESEARCH 63, 4533– 4537, August 1, 2003] Opposite Effects of Modifiers of the Apc Min Mutation in Intestine and Mammary Gland 1 Alina Czarnomska, Elzbieta Krysiak, Joanna Piskorowska, Miroslawa Sitarz, Kazimiera Pysniak, Toma ´s ˇ Pilc ˇı ´k, and Peter Demant 2 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.] ABSTRACT 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 muta- tion, affecting the Wnt pathway. The presence of Apc Min increased con- siderably 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 path- way-mediated tumorigenesis will help to understand the interactions be- tween germ-line encoded allelic differences in susceptibility genes and the spectrum of somatic mutations in tumor cells. INTRODUCTION Colorectal cancer and breast cancer are collectively responsible for the largest part of cancer-related deaths. In humans, the genetic factors affect both the sporadic and hereditary forms of these cancers (1, 2). Identification of genes that modify the development of these cancers is important for the unraveling of the pathways of the neoplastic process, as well as for the understanding of the role of the host genotype for the propensity of cancer development and progression. The development of nonfamilial, “sporadic,” cancer is influenced by many genes (3). In this respect is cancer similar to other common (nonfamilial) diseases, including cardiovascular, metabolic, and in- fectious diseases. With the infectious diseases, it has been shown that susceptibility is controlled by multiple loci, and for both Leishmani- asis (4, 5) and Lyme disease (6), it was demonstrated that different loci affect different aspects of the disease phenotype, thus permitting to link heterogeneity of the disease with the host genotype. Such associations between heterogeneity of the disease and genetic poly- morphisms of the host are likely to apply to all types of diseases, including cancer. Obviously, the understanding of the genetic factors regulating different aspects of the cancer phenotype would be impor- tant for the assessment of future disease progression and selection of optimal therapy. The accumulation of specific somatic alterations in cancer cells is linked with the probability of malignant progression. However, it is not clear to what extent the genes of the host modify the effects of such alterations. Definition of the contribution of such genomic modifiers would considerably improve the interpretation of the genetic profiling of cancer. Animal models provide the necessary versatility for such studies (7). One of them is the Apc Min mutation in Apc gene, the mouse homologue of the human APC gene (8). C57BL/6J mice that carry Apc Min mutation develop numerous intestinal tumors at an early age and rarely survive beyond 150 days of age (9). In addition, C57BL/6 Min/+ females tend to develop mammary tumors (9, 10). Min is a fully penetrant dominant mutation mapped to proximal chromosome 18 (11), and it is a homozygous lethal (12). The Min/+ mice are a good model for studies of both induction and prevention of inherited and sporadic cancers (9, 13). The development of adenomas in intes- tines of Min/+ mice is influenced by genetic background. The dif- ference is probably attributable to several “modifier” genes, carried by different inbred strains. One of them is the semidominant Mom1 (14 –16) on chromosome 4. The second modifier Mom2 on chromo- some 18 is the result of a spontaneous mutation (17). Kohlhepp et al. (18, 19) identified in ENU-treated Min/+ mice a modifier effect on the resistance to mammary and intestinal tumors linked to ROSA26 insertion. As the modifier effect has been noted only in ENU-treated mice, it has not been formally ruled out that it affects the response of these tissues to ENU treatment. The multiplicity and invasiveness of intestinal adenomas of Apc Min mice are enhanced besides Mom1 susceptible allele also by p53 deficiency (20). Genetic background affects also development of mammary tumors in Min/+ mice (21). It would be important for the understanding of the nature of modifier genes to compare their impact on the effects of the Apc Min mutation in different tissues. We compared, therefore, the impact of the host genotype on tumor development in mammary gland and intestine of Min/+ mice, using the special tool of genetic dissection of multigenic traits, the RCSs (22, 23). In the series of homozygous OcB/Dem RCSs, each strain carries a different random portion of 12.5% of the genes of the strain B10.O20/Dem (B10.O20) on the genetic back- ground of the O20/A (O20) strain. In this way, the different OcB strains contain different combinations of possible modifier genes and therefore could differently modify the tumorigenic effects of the Apc Min mutation. In the present study, we show that the mice of OcB strains exhibit in the presence of Min mutation different patterns of susceptibility to mammary and intestinal tumors. We also show that different OcB strains exhibit preferentially certain types of mammary tumors. MATERIALS AND METHODS Mice. RCSs of the OcB/Dem series (described in Refs. 22 and 23), B10.O20 mice, and the congenic strain BALB/cMin/+ , produced by 15 backcrosses of the Min mutation from the C57BL/6 strain have been main- Received 1/30/03; accepted 5/22/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by European Commission Grant ERB IC 15 CT 98-317. 2 To whom requests for reprints should be addressed, at Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-1399; Fax: (716) 845-5908; E-mail: peter.demant@roswellpark.org. 3 The abbreviations used are: Min, multiple intestinal neoplasia; Mom, modifier of Min; ENU, ethylnitrosourea; RCS, recombinant congenic strain. 4533 Research. on November 25, 2021. © 2003 American Association for Cancer cancerres.aacrjournals.org Downloaded from