Carcinogenesis Advance Access published online on October 7, 2004
Carcinogenesis, doi:10.1093/carcin/bgh298
© 2004 by Oxford University Press
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1 Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tuebingen, Wilhelmstrasse 56, 72074 Tuebingen, Germany
* To whom correspondence should be addressed. E-mail: michael.schwarz{at}uni-tuebingen.de.
Phenobarbital (PB) is a model tumor promoter in rodent liver. In the mouse, the promotional effect of PB results from a selective stimulation of clonal outgrowth of hepatocytes harboring activating mutations in the
Revised September 27, 2004
Accepted September 27, 2004
CARCINOGENESIS
A
-catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors
Abstract 
-catenin (catnb) gene. Glutamine synthetase, a downstream target in the Wnt/-catenin/TCF signaling pathway, is strongly upregulated in catnb-mutated mouse liver tumors and may serve as a marker for their identification. Here we show that the levels of several cytochrome P450 (CYP) isoenzymes are also altered in GS-positive liver tumors. Immunohistochemical and Western blotting analyses demonstrated that GS-positive, catnb-mutated tumors showed levels of CYP1A, CYP2B, CYP2C, and CYP2E1 which were similar or slightly enhanced in comparison to nontumoral liver tissue. This contrasts tumors without catnb-mutations which exhibited decreased levels of these CYP isoforms. Real-time RT-PCR revealed that the differences in CYP levels in the tumors corresponded to changes in the respective mRNAs. Mouse hepatoma cells were transiently transfected with an expression vector encoding a S33Y-mutated -catenin protein, which was functional with regard to transactivation of a -catenin/TCF-responsive (topflash) reporter construct. Cotransfection with luciferase reporter vectors containing either the regulatory upstream sequence of the CYP2B1 gene or three dioxin-responsive core elements (DRE) were activated by S33Y--catenin. These results indicate that mutation of catnb leads to transcriptional activation of CYP isoenzymes in mouse liver tumors. Since CYPs are involved in both the activation and the inactivation of several clinically important anti-cancer drugs, our findings may be relevant for chemotherapy of human cancers, where activation of -catenin dependent signaling by mutation of the gene or alternative mechanisms is frequently observed.
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