Long-term exposure to elevated levels of circulating TIMP-1 but not mammary TIMP-1 suppresses growth of mammary carcinomas in transgenic mice

• Published in: Carcinogenesis (New York) 2004-09, Vol.25 (9), p.1735-1746
• Main Authors: Yamazaki, Masaharu, Akahane, Takemi, Buck, Todd, Yoshiji, Hitoshi, Gomez, Daniel E., Schoeffner, Daniel J., Okajima, Eijiro, Harris, Steven R., Bunce, Opal R., Thorgeirsson, Snorri S., Thorgeirsson, Unnur P.
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Albumins - genetics; Animals; Antigens, Polyomavirus Transforming - genetics; Apoptosis; basic fibroblast growth factor; bfgf; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; dimethylbenz[a]anthracene; DMBA; ECM; extracellular matrix; Female; Lung Neoplasms - blood; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - prevention & control; Mammary Tumor Virus, Mouse - genetics; matrix metalloproteinases; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Middle T antigen; MMPs; MMTV-LTR; mouse mammary tumor virus-long terminal repeat; Terminal Repeat Sequences - genetics; TIMP-1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; tissue inhibitor of metalloproteinases-1; Transgenes; Tumors; vascular endothelial growth factor; VEGF; wild-type
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh181

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.