Tr. Devereux et al., Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis, ONCOGENE, 18(33), 1999, pp. 4726-4733
beta-catenin activation, and subsequent upregulation of Wnt-signaling, is a
n important event in the development of certain human and rodent cancers. R
ecently, mutations in the beta-catenin gene in the region of the serine-thr
eonine glycogen kinase (GSK)-3 beta phosphorylation target sites have been
identified in hepatocellular neoplasms from humans and transgenic mice. In
this study we: examined 152 hepatocellular neoplasms from B6C3F1 mice inclu
ded in five chemical treatment groups and controls for mutations in the bet
a-catenin gene. Twenty of 29 hepatocellular neoplasms from mice treated wit
h methyleugenol had point mutations at codons 32, 33, 33 or 41. sites which
are mutated in colon and other cancers. Likewise, nine of 24 methylene chl
oride-induced hepatocellular neoplasms and 18 of 42 oxazepam-induced neopla
sms exhibited similar mutations. In contrast,only three of 18 vinyl carbama
te-induced liver tumors, one of 18 TCDD-induced liver tumors, and two of 22
spontaneous liver neoplasms had mutations in beta-catenin. Thus. there app
ears to be a chemical specific involvement of beta-catenin activation in mo
use hepatocellular carcinogenesis. Expression analyses using Western blot a
nd immunohistochemisty indicate that beta-catenin protein accumulates along
cell membranes following mutation. The finding of mutations in both adenom
as and carcinomas from diverse chemical treatment groups and the immunostai
ning of beta-catenin protein in an altered hepatocellular focus suggest tha
t these alterations are early events in mouse hepatocellular carcinogenesis
.