Carcinogenesis Advance Access originally published online on May 27, 2004
Carcinogenesis 2004 25(9):1735-1746; doi:10.1093/carcin/bgh181
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Carcinogenesis vol.25 no.9 © Oxford University Press 2004; all rights reserved.
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Long-term exposure to elevated levels of circulating TIMP-1 but not mammary TIMP-1 suppresses growth of mammary carcinomas in transgenic mice
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
Present addresses: 1 Nara Medical University, The Third Department of Internal Medicine, 840 Shiji-cho, Kashihara, Nara, Japan, 2 Department of Science and Technology, Quilmes National University, Buenos Aires, Argentina, 3 National Cancer Center Hospital, 1-1 Tsukiji, 5-Chrome, Chuo-ku, Tokyo 104-0045, Japan, 4 Pikeville School of Osteopathic Medicine, Pikeville, KY 41501, USA, 5 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 41501, USA and 6 Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
7 To whom correspondence should be addressed Email: thorgeiu{at}mail.nih.gov
Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates matrix metalloproteinase activity, acts as a growth stimulator and inhibits apoptosis. We developed transgenic mice to evaluate the relevance of circulating versus mammary TIMP-1 in mammary carcinogenesis. The transgene was placed under the control of the albumin (Alb) promoter for the production of large amounts of TIMP-1 in the liver and release into the systemic circulation to achieve chronically elevated blood levels. The initial 7,12-dimethylbenz[a]anthracene (DMBA) mammary carcinogenesis study showed greatly decreased tumor incidence in heterozygous Alb-TIMP-1 mice (25%), compared with their wild-type (wt) littermates (83.3%). Metastatic mammary carcinomas were induced in the Alb-TIMP-1 mice through breeding with mice expressing the polyomavirus Middle T antigen (MT) under the control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Both the mammary tumor burden and the incidence of lung metastases were lower in the Alb-TIMP-1/MMTV-MT mice than their MMTV-MT littermates. Analysis of the Alb-TIMP-1/MMTV-MT tumors showed evidence of decreased proliferative activity and inhibition of apoptosis, whereas microvascular density was not affected. Transgenic expression of TIMP-1 in mammary epithelial cells was accomplished by using MMTV-LTR. In contrast to the Alb-TIMP-1 mice, there was insignificant difference in the growth of both DMBA- and MT-induced mammary tumors between heterozygous MMTV-TIMP-1 mice and their wt littermates. The MT-induced mammary tumors of the MMTV-TIMP-1 mice were separated into ‘low’ and ‘high’ TIMP-1 expressing groups. The ‘high’ TIMP-1 expressing tumors exhibited significantly higher proliferative activity than the tumors of the MMTV-MT only mice, whereas the number of apoptotic cells and microvascular density were not different. The findings of this study show that circulating TIMP-1, but not mammary-derived TIMP-1, has growth suppressive effects on DMBA and MT-induced mammary carcinomas.
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