Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis.
Murine hepatocarcinogenesis requires growth hormone (GH). To determine if the GH-responsive transcription factor STAT5b (signal transducer and activator of transcription 5b) is also required, we compared the hepatic gene expression profiles of global Stat5b null mice to cancer-resistant mice mutant in the GH pathway-GH-deficient little and androgen receptor-null Tfm males. We found a high degree of overlap among Tfm, little, and Stat5b null males. The liver cancer susceptibility of global Stat5b null mice was assessed on three distinct genetic backgrounds: BALB/cJ (BALB), C57BL/6J (B6), and C3H/HeJ (C3H). The effect of Stat5b on hepatocarcinogenesis depended on the genetic background. B6 Stat5b null congenic males and females developed 2.4 times as many tumors as wild-type (WT) controls (P < 0.002) and the tumors were larger (P < 0.003). In BALB/c congenics, loss of STAT5b had no effect on either sex. C3H Stat5b null congenic males and females were resistant to liver cancer, developing 2.7- and 6-fold fewer tumors, respectively (P < 0.02, 0.01). These results provide the first example of a single gene behaving as both oncogene and tumor suppressor in a given tissue, depending only on the endogenous modifier alleles carried by different genetic backgrounds.
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Christopher C
CC
Oberley
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Andrea
A
Bilger
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Norman R
NR
Drinkwater
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D005260:Female; D000068617:Genetic Background; D013006:Growth Hormone / Q000235:genetics; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000235:genetics*
D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D013006:Growth Hormone
growth hormone; liver cancer; mouse genetics; sex hormones