Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases

Vincent Chabottaux, Nor Eddine Sounni, Caroline J Pennington, William R English, Frédéric van den Brûle, Silvia Blacher, Christine Gilles, Carine Munaut, Erik Maquoi, Carlos Lopez-Otin, Gillian Murphy, Dylan Edwards, Jean-Michel Foidart, Agnès Noel

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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)
Original languageEnglish
Pages (from-to)5165-5172
Number of pages8
JournalCancer Research
Issue number10
Publication statusPublished - 16 May 2006

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