Carcinogenesis Advance Access published online on August 17, 2006
Carcinogenesis, doi:10.1093/carcin/bgl138
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1 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, 60612
* To whom correspondence should be addressed. Clinical trials and laboratory-based studies indicate that the growth hormone/insulin-like growth factor-I (GH/IGF) 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 down regulation of GH signaling can substantially retard mammary cancer progression. We crossed the Laron mouse, in which the gene for the GH receptor/binding protein (GHR/BP) 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 vs. 3.2 ± 1.2) and volume (776.1 ± 284.4 vs. 50.5 ± 8.9 mm3). Furthermore, the frequency of mammary hyperplasias was significantly reduced in the TAg/Ghr-/- mice (15.0 ± 1.7 vs. 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.
Received May 4, 2006
Revised July 6, 2006
Accepted July 19, 2006
CANCER PREVENTION
Inhibition of estrogen independent mammary carcinogenesis by disruption of growth hormone signaling
Xiao Zhang 1, Rajendra G. Mehta 2, Daniel D. Lantvit 1, Karen T. Coschigano 3, John J. Kopchick 3, Jeffrey E. Green 4, Samad Hedayat 5, Konstantin T. Christov 6, Vera H. Ray 7, Terry G. Unterman 8, and Steven M. Swanson 9 *
2 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, 60612; Illinois Institute of Technology Research Institute, Chicago, IL 60616
3 Edison Biotechnology Institute and Department of Biomedical Sciences, Ohio University, Athens, OH
4 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD
5 Department of Math, Statistics, and Computer Science, University of Illinois at Chicago, Chicago, IL, 60612
6 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, 60612
7 Provident Hospital of Cook County, Chicago, IL
8 Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612; Department of Veterans Affairs Jesse Brown Medical Center, Chicago, IL, 60612
9 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, 60612; Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, 60612
Steven M. Swanson, E-mail: swanson{at}uic.edu
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