Abstract
Tissue inhibitors of matrix metalloproteinase (TIMPs) are multifunctional proteins with both matrix metalloproteinase (MMP) inhibitory effects and growth-regulatory activity. TIMPs inhibit MMP activity, suggesting a use for cancer gene therapy. However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice. Consistent with tumor stimulation, TIMP-4 up-regulates Bcl-2 and Bcl-X(L) protein. TIMP-4 also inhibits apoptosis in human breast cancer cells in vitro and mammary tumors in vivo. A synthetic MMP inhibitor BB-94 did not have such antiapoptotic effect. Analysis of TIMP-4 expression in human mammary specimens indicates that TIMP-4 protein is increased in mammary carcinoma cells compared with normal mammary epithelial cells. These data indicate an antiapoptotic activity in breast cancer cells and a tumor-stimulating effect of TIMP-4 when administrated systemically.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Breast / metabolism
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Breast / pathology
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Breast / physiology*
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cell Survival / genetics
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Cell Transformation, Neoplastic / genetics*
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DNA / administration & dosage*
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DNA / genetics
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Electroporation
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Female
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Genetic Therapy
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Humans
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Injections, Intramuscular
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Plasmids / administration & dosage
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Plasmids / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Rabbits
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Tissue Inhibitor of Metalloproteinase-4
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Tissue Inhibitor of Metalloproteinases / biosynthesis
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Tissue Inhibitor of Metalloproteinases / genetics
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Tissue Inhibitor of Metalloproteinases / physiology*
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Transplantation, Heterologous
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bcl-X Protein
Substances
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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Tissue Inhibitor of Metalloproteinases
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bcl-X Protein
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DNA