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p53 Transgenic Mice Are Highly Susceptible to 1, 2-Dimethylhydrazine-induced Uterine Sarcomas¹

Division of Human Cancer Genetics [Z. Z., J. L., M. Y.] and School of Public Health [Y. W.], The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210; Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [L. E. L.]; Laboratory of Women’s Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [R. W. W.]; and Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892 [R. A. L.]

p53 Transgenic mice were crossed with C57BL/6J mice to investigate whether a germ-line mutation in the p53 gene predisposes for tumorigenesis in mice. (C57BL/6J x UL53–3) F₁ mice were treated with 1,2-dimethylhydrazine (DMH), a colon carcinogen. The presence of a mutant p53 led to an increased incidence or multiplicity of uterine sarcomas, colon carcinomas, lung adenomas, and hepatomas in DMH-treated mice. The most significant effect of mutant p53 was the increased incidence of uterine sarcomas, which were found in 90% of p53^val135/wt mice but only seen in 10% of p53^wt/wt mice. After examination of 15 known p53 downstream target genes in uterine sarcomas and normal uteri, we found that expression of the Reprimo gene was significantly increased in normal uteri of p53^wt/wt mice but not in either normal uterus or uterine sarcomas of p53^val135/wt mice. In DMH-treated animals, long-term treatment with this chemopreventive agent, piroxicam, reduced colon carcinoma incidence and multiplicity in both p53^val135/wt or p53^wt/wt mice but did not affect the formation of uterine sarcomas, lung adenomas, or hepatomas. These results demonstrate a tissue-specific enhancement of tumorigenesis in multiple organs by the mutant p53 transgene and additionally support the utility of (C57BL/6J x UL53–3) F₁ mice for chemoprevention studies.

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