Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh083
© 2004 by Oxford University Press
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CANCER BIOLOGY
1 Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258
* Corresponding author. E-mail: snorri_thorgeirsson{at}nih.gov.
Received 7 October 2003
; revised 7 January 2004
; accepted 10 January 2004
Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/TGF-
Activation of
-catenin provides proliferative and invasive advantages in c-myc/TGF-
hepatocarcinogenesis promoted by phenobarbital
transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring 
-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/-catenin signaling is involved in both antiapoptotic and proliferative processes, we now have extended our analysis to investigate whether promotion by PB affects the occurrence of -catenin mutations in c-myc/TGF--driven tumors. The frequency of -catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF- mice treated with PB (15/28; 53.6%) as compared to that in control HCCs (2/28; 7.1%). Furthermore, an intact -catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF- untreated mice displayed loss of heterozygosity at the -catenin locus. Strikingly, in the majority of PB-treated HCCs -catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). -catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All -catenin positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with -catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of -catenin in c-myc/TGF- HCCs. -catenin activation confers additional growth and invasive advantages in a model of liver cancer already accelerated by synergistic activity of the c-myc and TGF- transgenes.-catenin, HCC, phenobarbital, transgenic mouse models
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