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Membrane-Type 4 Matrix Metalloproteinase Promotes Breast Cancer Growth and Metastases

¹ Laboratory of Tumor and Development Biology, Centre de Recherche en Cancérologie Expérimentale, Center for Biomedical Integrative Genoproteomics, University of Liège; ² Department of Gynecology CHU, Liège, Belgium; ³ School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom; ⁴ Department of Oncology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom; and ⁵ Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain

Requests for reprints: Agnes Noël, Laboratory of Tumor and Development Biology, University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège. Phone: 32-4-366-24-53; Fax: 32-4-366-29-36; E-mail: agnes.noel{at}ulg.ac.be.

Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been well documented, the significance of other MT-MMPs is rather unknown. We have investigated the involvement of MT4-MMP, a glycosylphosphatidylinositol–anchored protease, in breast cancer progression. Interestingly, immunohistochemical analysis shows that MT4-MMP production at protein level is strongly increased in epithelial cancer cells of human breast carcinomas compared with normal epithelial cells. Positive staining for MT4-MMP is also detected in lymph node metastases. In contrast, quantitative reverse transcription-PCR analysis reveals similar MT4-MMP mRNA levels in human breast adenocarcinomas and normal breast tissues. Stable transfection of MT4-MMP cDNA in human breast adenocarcinoma MDA-MB-231 cells does not affect in vitro cell proliferation or invasion but strongly promotes primary tumor growth and associated metastases in RAG-1 immunodeficient mice. We provide for the first time evidence that MT4-MMP overproduction accelerates in vivo tumor growth, induces enlargement of i.t. blood vessels, and is associated with increased lung metastases. These results identify MT4-MMP as a new putative target to design anticancer strategies. (Cancer Res 2006; 66(10): 5165-72)

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