Carcinogenesis Advance Access originally published online on August 17, 2006
Carcinogenesis 2007 28(1):143-150; doi:10.1093/carcin/bgl138
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Inhibition of estrogen-independent mammary carcinogenesis by disruption of growth hormone signaling
1 Department of Medicinal Chemistry and Pharmacognosy University of Illinois at Chicago, Chicago, IL 60612
2 Department of Surgical Oncology University of Illinois at Chicago, Chicago, IL 60612
3 Department of Mathematics, Statistics and Computer Science University of Illinois at Chicago, Chicago, IL 60612
4 Department of Medicine University of Illinois at Chicago, Chicago, IL 60612
5 Department of Veterans Affairs Jesse Brown Medical Center, Chicago IL 60612
6 Illinois Institute of Technology Research Institute, Chicago IL 60616
7 Edison Biotechnology Institute and Department of Biomedical Sciences, Ohio University Athens, OH
8 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute Bethesda, MD
9 Provident Hospital of Cook County, Chicago IL, USA
*To whom correspondence and requests for reprints should be addressed at: Department of Medicinal Chemistry and Pharmacognosy (M/C 781), University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, USA. Tel: +1 312 996 0842; Fax: +1 312 996 7107 Email: swanson{at}uic.edu
Clinical trials and laboratory-based studies indicate that the growth hormone/insulin-like growth factor-I axis may affect the development of breast cancer. The purpose of the present investigation was to develop a genetic model of mammary cancer to test the hypothesis that downregulation of GH signaling can substantially retard mammary cancer progression. We crossed the Laron mouse, in which the gene for the GH receptor/binding protein has been disrupted, with the C3(1)/TAg mouse, which develops estrogen receptor 
negative mammary cancers. All mice used in our experiments were heterozygous for the large T antigen (TAg) and either homozygous wild-type for GHR (Ghr+/+) or null for GHR (Ghr–/–). Compared with the TAg/Ghr+/+ mice, the TAg/Ghr–/– mice showed delayed mammary cancer latency with significantly decreased multiplicity (9.8 ± 1.4 versus 3.2 ± 1.2) and volume (776.1 ± 284.4 versus 50.5 ± 8.9 mm3). Furthermore, the frequency of mammary hyperplasias was significantly reduced in the TAg/Ghr–/– mice (15.0 ± 1.7 versus 6.8 ± 1.7). To establish that these mammary cancers were estrogen-independent, 12-week-old TAg/Ghr+/+ mice, which lack visible hyperplasia, were either ovariectomized (ovx) or sham operated (sham). Compared with the sham group, ovariectomy resulted in no difference in the frequency of mammary hyperplasia, mammary tumor latency, incidence, multiplicity or tumor size. Together, these data demonstrate that the disruption of GH signaling significantly retards TAg-driven mammary carcinogenesis, and suggest that disrupting GH signaling may be an effective strategy to inhibit the progression of estrogen-independent breast cancer.
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