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Science 11 September 1987:
Vol. 237. no. 4820, pp. 1309 - 1316
DOI: 10.1126/science.3629242
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Articles

Science, Vol 237, Issue 4820, 1309-1316
Copyright © 1987 by American Association for the Advancement of Science

articles

Activated oncogenes in B6C3F1 mouse liver tumors: implications for risk assessment

SH Reynolds, SJ Stowers, RM Patterson, RR Maronpot, SA Aaronson, and MW Anderson

The validity of mouse liver tumor end points in assessing the potential hazards of chemical exposure to humans is a controversial but important issue, since liver neoplasia in mice is the most frequent tumor target tissue end point in 2-year carcinogenicity studies. The ability to distinguish between promotion of background tumors versus a genotoxic mechanism of tumor initiation by chemical treatment would aid in the interpretation of rodent carcinogenesis data. Activated oncogenes in chemically induced and spontaneously occurring mouse liver tumors were examined and compared as one approach to determine the mechanism by which chemical treatment caused an increased incidence of mouse liver tumors. Data suggest that furan and furfural caused an increased incidence in mouse liver tumors at least in part by induction of novel weakly activating point mutations in ras genes even though both chemicals did not induce mutations in Salmonella assays. In addition to ras oncogenes, two activated raf genes and four non-ras transforming genes were detected. The B6C3F1 mouse liver may thus provide a sensitive assay system to detect various classes of proto-oncogenes that are susceptible to activation by carcinogenic insult. As illustrated with mouse liver tumors, analysis of activated oncogenes in spontaneously occurring and chemically induced rodent tumors will provide information at a molecular level to aid in the use of rodent carcinogenesis data for risk assessment.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genetic Alterations in K-ras and p53 Cancer Genes in Lung Neoplasms from B6C3F1 Mice Exposed to Cumene.
H.-H. L. Hong, T.-V. T. Ton, Y. Kim, N. Wakamatsu, N. P. Clayton, P.-C. Chan, R. C. Sills, and S. A. Lahousse (2008)
Toxicol Pathol 36, 720-726
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Hepatocarcinogenesis in Mice with {beta}-Catenin and Ha-Ras Gene Mutations.
N. Harada, H. Oshima, M. Katoh, Y. Tamai, M. Oshima, and M. M. Taketo (2004)
Cancer Res. 64, 48-54
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Cyclin D1 over-expression correlates with {beta}-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3{beta} and ERK1/2 in mouse hepatic carcinogenesis.
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Carcinogenesis 24, 435-442
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Food Mutagens.
R. Goldman and P. G. Shields (2003)
J. Nutr. 133, 965S-973
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Comparative Prevalence, Multiplicity, and Progression of Spontaneous and Vinyl Carbamate-Induced Liver Lesions in Five Strains of Male Mice.
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Toxicol Pathol 30, 599-605
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Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-{beta}1 and Ha-Ras: steps towards invasiveness.
J. Gotzmann, H. Huber, C. Thallinger, M. Wolschek, B. Jansen, R. Schulte-Hermann, H. Beug, and W. Mikulits (2002)
J. Cell Sci. 115, 1189-1202
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Nonrandom Cytogenetic Alterations in Hepatocellular Carcinoma from Transgenic Mice Overexpressing c-Myc and Transforming Growth Factor-{alpha} in the Liver.
L. M. Sargent, X. Zhou, C. L. Keck, N. D. Sanderson, D. B. Zimonjic, N. C. Popescu, and S. S. Thorgeirsson (1999)
Am. J. Pathol. 154, 1047-1055
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The Use of Immunohistochemistry for Evaluating the Liver.
W. C. Hall and J. L. Rojko (1996)
Toxicol Pathol 24, 4-12
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Current Knowledge of Mechanisms of Carcinogenicity: Genotoxins versus Non-genotoxins.
I.F.H. Purchase (1994)
Human and Experimental Toxicology 13, 17-28
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Furan-Induced Hepatic Cholangiocarcinomas in Fischer 344 Rats.
R. R. Maronpot, H. D. Giles, D. J. Dykes, and R. D. Irwin (1991)
Toxicol Pathol 19, 561-570
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Carcinogens and human health: Part 1.
F. Perera (1990)
Science 250, 1644-1646
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Oncogene Activation in Multistage Carcinogenesis.
S. J. Garte (1989)
International Journal of Toxicology 8, 241-243
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