The growth hormone-deficient Spontaneous Dwarf rat is resistant to chemically induced mammary carcinogenesis.
Recent epidemiologic studies have suggested that the growth hormone (GH)/insulin-like growth factor I axis plays an important role in human breast cancer. The purpose of the present study was to evaluate the function of GH in rat mammary carcinogenesis, a model that closely recapitulates human breast cancer biology. The Spontaneous Dwarf rat (SDR) arose from the Sprague-Dawley rat and harbors a mutation in its GH gene yielding undetectable levels of a severely truncated protein not capable of binding to the GH receptor. When female rats of either strain were exposed to the direct-acting carcinogen N-methyl-N-nitrosourea, all wild-type rats (n = 10) developed multiple mammary cancers (5.3/rat). In contrast, SDR rats (n = 15) developed only three cancers (0.2/rat) and these were very small (<6 mm3). In another experiment, SDRs were backcrossed with wild-type Sprague-Dawley rats and the progeny were exposed to the indirect-acting carcinogen 7,12-dimethylbenz[a]anthracene. Progeny that were either homo- or heterozygous for the wild-type GH gene developed approximately 4 mammary tumors/rat, respectively. In contrast, SDR progeny developed only 0.21 tumors/rat. Mammary glands of SDRs had substantially less alveolar development compared with wild-type, yet ductal branching was similar in the two strains. Infusion of rat GH to SDRs induced mammary epithelial cell proliferation and alveolar development similar to that of wild-type rats. Taken together, these results demonstrate an important role for GH in alveolar development in the virgin rat, and provide the first direct evidence that GH plays a critical role in mammary carcinogenesis.
Swanson
Steven M
SM
Program for Collaborative Research in the Pharmaceutical Sciences and the Center for Pharmaceutical Biotechnology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. swanson@uic.edu
Unterman
Terry G
TG
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology; D002273:Carcinogens; D002455:Cell Division; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000235:genetics; D019382:Human Growth Hormone / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008770:Methylnitrosourea; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D019382:Human Growth Hormone; D015127:9,10-Dimethyl-1,2-benzanthracene; D007334:Insulin-Like Growth Factor I; D008770:Methylnitrosourea; D013006:Growth Hormone