Journal Article

The growth hormone-deficient Spontaneous Dwarf rat is resistant to chemically induced mammary carcinogenesis

Steven M. Swanson and Terry G. Unterman

in Carcinogenesis

Volume 23, issue 6, pages 977-982
Published in print June 2002 | ISSN: 0143-3334
Published online June 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.6.977
The growth hormone-deficient Spontaneous Dwarf rat is resistant to chemically induced mammary carcinogenesis

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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 ~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.

Keywords: BrdU, bromodeoxyuridine; DMBA, 7,12-dimethylbenz[a] anthracene; IGF, insulin-like growth factor; MNU, N-methyl-N-nitrosourea; SDR, the Spontaneous Dwarf rat.

Journal Article.  5282 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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