The little mutation suppresses DEN-induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility.
In mice, the sex difference in susceptibility to hepatocarcinogenesis results from the tumor promoting activity of testosterone and from the inhibition of tumor promotion by ovarian hormones. We investigated the role of growth hormone in the sex-dependent regulation of susceptibility, because sex hormones are known to regulate the temporal pattern of growth hormone secretion and subsequent sex differences in liver gene expression. We found that in both males and females, wild-type mice developed significantly more tumors than growth hormone-deficient, C57BL/6J-lit/lit (B6-lit/lit) mutant mice following perinatal treatment with the carcinogen N,N-diethylnitrosamine (DEN). B6 wild-type males developed 36-59-fold more liver tumors per animal than age matched B6-lit/lit males and wild-type females developed 11-fold more tumors than B6-lit/lit females. We bred the little mutation onto the more susceptible C57BR/cdJ (BR) and C3H/HeJ (C3H) strains to assess the effect of growth hormone deficiency on hepatocarcinogenesis on additional genetic backgrounds. Growth hormone deficiency suppressed liver tumor development to <1% in males of each strain and in BR strain females. In B6 and C3H females, growth hormone deficiency caused 2-4-fold reductions in the volume fraction of the liver occupied by preneoplastic lesions. Furthermore, in contrast to wild-type strains, neither gonadectomy nor strain background significantly affected susceptibility in lit/lit mice, as mean liver tumor multiplicities ranged from 0 to 0.24 +/- 0.44 and the volume fraction of preneoplastic lesions ranged from 0.21 +/- 0.22 to 0.61 +/- 1.9%. These results demonstrate that both strain and sex hormonal effects on susceptibility to liver carcinogenesis are dependent on wild-type levels of growth hormone.
Bugni
J M
JM
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706, USA.
Poole
T M
TM
Drinkwater
N R
NR
D000818:Animals; D001973:Bromodeoxyuridine; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004052:Diethylnitrosamine; D005260:Female; D020022:Genetic Predisposition to Disease; D013006:Growth Hormone / Q000172:deficiency / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012737:Sex Factors
D002273:Carcinogens; D004052:Diethylnitrosamine; D013006:Growth Hormone; D001973:Bromodeoxyuridine