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Tissue Inhibitor of Metalloproteinases-1 Stimulates Gene Expression in MDA-MB-435 Human Breast Cancer Cells by Means of its Ability to Inhibit Metalloproteinases

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Summary

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely expressed, secreted protein that functions primarily to inhibit members of a large family of metalloproteinases (MPs). Because of the ability of TIMP-1 to inhibit MPs, it functions in many of the same pathophysiological processes as these enzymes, e.g. wound healing, ovulation, angiogenesis, and cancer cell metastasis. TIMP-1 can also stimulate proliferation ([3H]thymidine incorporation) and cellular anabolic processes (Alamar Blue reduction). This stimulation has been shown to be dependent on the MP-inhibitory ability of TIMP-1 in the human breast cancer cell line MDA-MB-435 (Porter et al., Br J Cancer 90: 463, 2004). To shed light on the mechanism by which TIMP-1 stimulates cellular anabolic processes, an oligonucleotide microarray analysis was performed over a time course of TIMP-1 treatment of MDA-MB-435 cells. Fifteen genes whose mRNAs were differentially regulated were identified. Six (Importin-7, MGC10471, FOXC1, subunit p20 of Arp2/3 complex, mitochondrial ribosomal protein L32, and the serine/threonine kinase-4 (MST1)) of these genes were confirmed by quantitative real time PCR. These same mRNAs were shown to be regulated by the synthetic hydroxamate MP-inhibitor GM6001 but not by its inactive derivative GM6001*, suggesting that the differential regulation occurs through the MP-inhibitory ability of TIMP-1. These results suggest a complex action of TIMP-1 on cancer cells mediated by constitutively active cell surface metalloproteinases that release factors regulating cell signaling pathways; they may account for the paradoxical observation that elevated levels of TIMP-1 in tumors can correlate with an adverse prognosis.

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Authors and Affiliations

  1. The Graduate Program in Microbiology and Molecular Genetics, Nelson Laboratories, Rutgers University, Piscataway, NJ, USA

    Joseph F. Porter & David T. Denhardt

  2. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Shashi Sharma & David T. Denhardt

  3. W.M. Keck Center for Collaborative Neuroscience, Nelson Laboratories, Rutgers University, Piscataway, NJ, USA

    Donna L. Wilson & Ronald P. Hart

  4. Rutgers College, New Brunswick, NJ, USA

    Maya A. Kappil

  5. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA

    Ronald P. Hart & David T. Denhardt

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  1. Joseph F. Porter
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  2. Shashi Sharma
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Correspondence to David T. Denhardt.

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Porter, J.F., Sharma, S., Wilson, D.L. et al. Tissue Inhibitor of Metalloproteinases-1 Stimulates Gene Expression in MDA-MB-435 Human Breast Cancer Cells by Means of its Ability to Inhibit Metalloproteinases. Breast Cancer Res Treat 94, 185–193 (2005). https://doi.org/10.1007/s10549-005-7728-4

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