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Laboratory of Animal Developmental Biotechnology, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea [H-Y. H., M-S. N., T-H. L., K-K. L., D-Y. Y.]; Research Institute of Medical Science, Catholic University of Korea, Seoul 137-040, Korea [J-W. L., Z-Y. R.]; Departments of Pathology [H-B. M.] and Surgery [B-J. S.], School of Medicine, Wonkwang University, Iksan 570-749, Korea; Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920, Japan [H. S.]; and Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108-639, Japan [M. S.]
To investigate the role of membrane-type matrix metalloproteinase-1 (MT1-MMP) in mammary gland development and tumorigenesis, transgenic mice overexpressing MT1-MMP in mammary gland under the control of the mouse mammary tumor virus long terminal repeat-promoter were generated. The mouse mammary tumor virus/MT1-MMP transgenic mice displayed abnormalities in 82% of female mammary glands. The abnormalities were verified as lymphocytic infiltration, fibrosis, hyperplasia, alveolar structure disruption, dysplasia, and adenocarcinoma. Northern and reverse transcription-PCR analyses demonstrated that MT1-MMP mRNA was overexpressed in mammary glands exhibiting abnormalities. Western blot analysis and immunohistochemical studies have revealed that the protein expression level was also increased in these glands. In addition, the ß-casein gene as a functional epithelial cell marker was poorly expressed in the mammary glands of transgenic mice exhibiting abnormalities. Gelatin zymography showed significantly increased MMP-2 activation in these mammary glands. These results showed that overexpression of MT1-MMP induced remodeling of the extracellular matrix and tumor formation in the mammary glands of transgenic mice. Therefore, we suggest that overexpression of MT1-MMP may play a key role in development and tumorigenesis in mammary glands.
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