Carcinogenesis Advance Access originally published online on December 24, 2005
Carcinogenesis 2006 27(5):1074-1080; doi:10.1093/carcin/bgi329
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Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor 
to Wy-14,643-induced liver tumorigenesis
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, 1 Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA and 2 Department of Pathology, Northwestern University School of Medicine, Chicago, IL 60611, USA
* To whom correspondence should be addressed at: Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892, USA. Tel: +1 301 496 9067; Fax: +1 301 496 8419; Email: fjgonz{at}helix.nih.gov
Peroxisome proliferators, such as lipid-lowering fibrate drugs, are agonists for the peroxisome proliferator-activated receptor 
(PPAR). Sustained activation of PPAR leads to the development of liver tumors in rodents. Paradoxically, humans appear to be resistant to the induction of peroxisome proliferation and development of liver tumors by peroxisome proliferators. To examine the species differences in response to peroxisome proliferators, a PPAR humanized mouse (hPPAR) was generated, in which the human PPAR was expressed in liver under control of the Tet-OFF system. To evaluate the susceptibility of hPPAR mice to peroxisome proliferator-induced hepatocarcinogenesis, a long-term feeding study of Wy-14,643 was carried out. hPPAR and wild-type (mPPAR) mice were fed either a control diet or one containing 0.1% Wy-14,643 for 44 and 38 weeks, respectively. Gene expression analysis for peroxisomal and mitochondrial fatty acid metabolizing enzymes revealed that both hPPAR and mPPAR were functional. However, the incidence of liver tumors including hepatocellular carcinoma was 71% in Wy-14,643-treated mPPAR mice, and 5% in Wy-14,643-treated hPPAR mice. Upregulation of cell cycle regulated genes such as cd1 and Cdks were observed in non-tumorous liver tissue of Wy-14,643-treated mPPAR mice, whereas p53 gene expression was increased only in the livers of Wy-14,643-treated hPPAR mice. These findings suggest that structural differences between human and mouse PPAR are responsible for the differential susceptibility to the peroxisome proliferator-induced hepatocarcinogenesis. This mouse model will be useful for human cancer risk assessment of PPAR ligands.
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