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Associate Professor Erik Thompson
Invasion & Metastasis Unit, Department of Surgery
University of Melbourne
Clinical Sciences Building, 29 Regent Street, Fitzroy, Vic 3065
Email: rik@medstv.unimelb.edu.au
Tel: +61-3-9288 2569
Fax: +61-3-03 9288 2605

We are interested in the role that matrix metalloproteinases (MMPs) play in breast cancer progression. We are especially interested in membrane-type MMP-1 (MT1-MMPs), which is important for activation of pro-MMP-2. Pro-MMP-2 is the latent form of MMP-2 secreted by both normal cells and cancer cells. It is kept latent by the pro-domain, which is cleaved by MT1-MMP to allow enzymatic activity. Although this is a much-studied aspect of MT1-MMP, more recent studies have examined the direct effects of MT1-MMP on various molecules and cellular processes. MT1-MMP is part of a suite of altered proteases and cell surface receptors which accompanies the change from a benign cancer cell to a malignant one. MT1-MMP transfection causes increased growth rate of breast cancers, and stimulates the invasiveness of various cell types in vitro. Similarly, knock-down of MT1-MMP blocks in vitro invasion. Identification of MT1-MMP substrates using degradomics may yield important clues as to the mechanisms of cancer invasion.
Also, more globally, we have found that broad-spectrum inhibition of MMPs in the MDA-MB-231 human breast cancer xenograft model causes dramatic reduction in the growth of the primary tumour when inoculated into the mammary fat pad, and also retards the process of bone metastasis after arterial inoculation of the cells intra-cardially. The specific MMPs responsible for this are not well elucidated, although we have identified potential candidates using quantitative RT-PCR. Degradomic analysis of these tumours before and after inhibition may provide clues as to the cleavage targets for this class of enzymes, and may help identify the most active MMP species.
Mark Waltham
Zena Werb
Motoharu Seiki
Chris Overall
Rafael Fridman
David Shalinsky
Angus M. Tester, Mark Waltham, Se-Jeong Oh, Seog-Nyeon Bae, Margaret M. Bills, Emma C. Walker, Francis G. Kern, William G. Stetler-Stevenson, Marc E. Lippman and Erik W. Thompson. ProMMP-2 Transfection Increases Orthotopic Primary Growth and Experimental Metastasis of MDA-MB-231 Human Breast Cancer Cells in Nude Mice. Cancer Research, In Press. 2004.

Sounni, N.E., Devy, L., Hajitou, A., Frankenne, F., Munaut, C., Gilles, C., Deroanne, C., Thompson, E.W., Foidart, J.M., and Noel, A. MT1-MMP expression promotes tumor growth and angiogenesis through an upregulation of vascular endothelial growth factor expression. FASEB J. 16(6):555-64 2002.

Marc A. Lafleur, Angus M. Tester, and Erik W. Thompson. Selective involvement of TIMP-2 in the second activational cleavage of MMP-2: Refinement of the pro-MMP-2 activation mechanism. FEBS Letters 553: 457-463, 2003.

Ruangpanit, N., Price, J.T., Holmbeck, K., Birkedal-Hansen, H., G_nzler, V., Huang, X., Chan, D., Bateman J.F., and Thompson, E.W. MT1-MMP-dependent and independent regulation of Gelatinase A activation in long-term, ascorbate-treated fibroblast cultures: Regulation by fibrillar collagen. Exp. Cell Res., 272: 109-118, 2002.

Tester, A.M., Ruangpanit, N., Anderson, R.L., and Thompson, E.W. MMP-9 secretion and MMP-2 activation distinguish invasive and metastatic sublines of a mouse mammary carcinoma system showing epithelial-mesenchymal transition traits. Clin. Exp. Metastasis. 18: 553-560, 2001.

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