The use of a bitransgenic mouse model for cancer is an effective approach for studying the impact of specific carcinogens and the occurrence of tissue-specific lesions. We studied the novel p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) mouse model because these mice contain a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele, both of which occur frequently in human cancers. Our aim was to characterize the short-term control and chemically induced tumor spectrum in this novel model. Mice were placed on basal semipurified diet containing 20% soy protein for 2 weeks prior to random allocation to groups. Subsequently, 15 male and 15 female mice were administered corn oil vehicle alone or containing benzo(a)pyrene (20 mg/kg body weight) via oral gavage 2 times per week for 10 weeks with subsequent observation for 18 weeks. Mice exhibited lesions characteristic of FVB/N, p53 heterozygous and Tg.AC mouse models. However, an array of unique, novel lesions were observed including uterine leiomyosarcomas, mammary gland carcinomas, mammary squamous cell carcinomas, and parotid salivary gland carcinomas suggesting tissue-specific interactions of the 2 genotypes. Thus, this bitransgenic model may provide further insight into the mechanistic interaction of 2 genes commonly mutated in neoplasia.
Blackshear, P.E. (2001). Genetically engineered rodent models of mammary gland carcinogenesis: an overview. Toxicol Pathol29, 105—16.
2.
Cardiff, R.D., Leder, A., Kuo, A., Pattengale, P.K., and Leder, P. (1993). Multiple tumor types appear in a transgenic mouse with the RAS oncogene. Am J Path142, 1199—207.
3.
Dardick, I., Burford-Mason, A.P., Garlick, D.S., and Carney, W.P. (1992). The pathobiology of salivary gland. II. morphological evaluation of acinic cell carcinomas in the parotid gland of male transgenic (MMTV/v-Ha-ras) mice as a model for human tumours. Virchows Arch A Pathol Anat Histopathol421, 105—13.
4.
Donehower, L.A., Harvey, M., Vogel, H., McArthur, M.J., Montgomery, C.A., Park, S.H., Thompson, T., Ford, R.J., and Bradley, A. (1995). Effects of genetic background on tumorigenesis in p53-deficient mice. Mol Carc14, 16—22.
5.
Hakura, A., Tsutsui, Y., Sonoda, J., Kai, J., Imade, T., Shimada, M., Sugihara, Y., and Mikami, T. (1998). Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta Mouse) . Mut Res398, 123—30.
6.
Hansen, L.A., Trempus, C.S., Mahler, J.F., and Tennant, R.W. (1996). Association of tumor development with increased cellular proliferation and transgene expression, but not c-Ha-ras mutations . Carcinogenesis17, 1825—33.
7.
Hollstein, M., Sirdansky, D., Vogelstein, B., and Harris, C.C. (1991). p53 mutations in human cancers. Science253, 49—53.
8.
Hundley, J.E., Koester, S.K., Troyer, D.A., Hilsenbeck, S.G., Subler, M.A., and Windle, J.J. (1997). Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol Cell Biol17, 723—31.
9.
Hursting, S.D., Slaga, T.J., Fischer, S.M., DiGiovanni, J., and Phang, J.M. (1999). Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst91, 215—25.
10.
Kantz, D.C., Lacks, G.D., and Cannon, R.E. (1999). Chemiluminescent-based method for genotyping Tg.AC responder mice. Biotechniques27, 278—80.
11.
Kosinska, W., von Pressentin, M., and Guttenplan, J.B. (1999). Mutagenesis induced by benzo(a)pyrene in lacZ mouse mammary and oral tissues: comparisons with mutagenesis in other organs and relationships to previous carcinogenicity assays. Carcinogenesis20, 1103—6.
12.
Kroese, E.D., Dortant, P.M., van Steeg, H., van Oostrom, C. T. M., ven Oort, C. W., van Kranen, H. J., de Vries, A., Wester, P. W., and van Kreijl, C. F. (1997). Use of Eu-PIM-1 transgenic mice for short-term in vivo carcinogenicity testing: lymphoma induction by benzo(a)pyrene, but not by TPA. Carcinogenesis18, 975—80.
13.
Leder, A., Kuo, A., Cardiff, R.D., Sinn, E., and Leder, P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin carcinogenesis. Proc Natl Acad Sci USA87, 9178—82.
14.
Lee, B.M., Kim, H.S., Kim, I.S., Ahn, M.Y., Chun, S.A., Yoo, S.D., and Park, Y.A. (2003). Ras transgene expression in TG-AC mice treated with benzo(a)pyrene. Biol Pharm Bull26, 733—5.
15.
Levine, A. (1997). p53, the cellular gatekeeper for growth and division . Cell88, 323—31.
16.
Li, B., Murphy, K.L., Laucirica, R., Kittrell, F., Medina, D., and Rosen, J.M. (1998). A transgenic mouse model for mammary carcinogenesis . Oncogene16, 997—1007.
17.
Loeb, K.R., and Loeb, L.A. (2000). Significance of multiple mutations in cancer. Carcinogenesis21, 379—85.
18.
MacLeod, K. (2000). Tumor suppressor genes. Curr Opin Gen Dev10, 81—93.
19.
MacLeod, K.F., and Jacks, T. (1999). Insights into cancer from transgenic mouse models . J Pathol187, 43—60.
20.
Mahler, J.F., Flagler, N.D., Malarkey, D.E., Mann, P.C., Haseman, J.K., and Easton, W. (1998). Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol Pathol26, 501—11.
21.
Mahler, J.F., Stokes, W., Mann, P.C., Takaoka, M., and Maronpot, R.R. (1996). Spontaneous lesions in aging FVB/N mice. Toxicol Pathol24, 710—6.
22.
Martin, K.R., Kari, F.W., Barrett, J.C., and French, J.E. (2000). N-acetyl-L-cysteine simultaneously increases mitogenesis and suppresses apoptosis in mitogen-stimulated B-lymphocytes from p53 haploinsufficient Tg.AC (v-Ha-ras) mice. In Vitro Mol Toxicol13, 237—47.
23.
Martin, K.R., Saulnier, M.J., Kari, F.W., Barrett, J.C., and French, J.E. (2002). Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic mice, but has no impact on malignant progression. Nutr Cancer43, 59—66.
Pritchard, J.B., French, J.E., Davis, B.J., and Haseman, J.K. (2003). The role of transgenic mouse models in carcinogen identification. Environ Health Perspect111, 444—54.
27.
Radany, E.H., Hong, K., Kesharvarzi, S., Lander, E.S., and Bishop, J.M. (1997). Mouse mammary tumor virus/v-Ha-ras transgenic-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome 4 . Proc Natl Acad Sci USA94, 8664—9.
28.
Robello, A., and Martinez, A.C. (1999). Ras proteins: recent advances and new functions . Blood94, 2971—80.
29.
Sanders, J.M., Burka, L.T., Chanas, B., and Matthews, H.B. (2001). Comparative xenobiotic metabolism between Tg.AC and p53+/ genetically altered mice and their respective wild types. Toxicol Sci61, 54—61.
30.
Singh, S.V., Benson, P.J., Hu, X., Pal, A., Xia, H., Srivastava, S.K., Awasthi, S., Zaren, H.A., Orchard, J.L., and Awasthi, Y.C. (1998). Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis . Cancer Lett128, 197— 204.
31.
Spalding, J.W., Stasiewicz, S., Fured-Machacek, M., Conner, F., Tice, R.R., and Tennant, R.W. (2000). Responses of transgenic mouse lines p53 () and Tg.AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci53, 213—23.
32.
Stefanou, D.G., Nonni, A.V., Kalpouzos, G., Evangelou, A., and Agnantis, N.J. (1998). Immunopenotype, ras oncogenes and p53 onco-supressor gene in benzo(a)pyrene induced malignant soft tissue tumours in Wistar rats . In Vivo12, 511—21.
33.
Tennant, R., Stasiewicz, S., Mennear, J., French, J.E., and Spalding, J.W. (1999). Genetically altered mouse models for identifying carcinogens. IARC Scientific Publications146, 123—50.
34.
Zachos, G., and Spandidos, D.A. (1998). Transcriptional regulation of the c-H-ras1 gene by the p53 protein is implicated in the development of human endometrial and ovarian tumors. Oncogene16, 3013—7.
