Abstract
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.