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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 10; pp. 5165 - 5172
• Main Authors: CHABOTTAUX, Vincent, EDDINE SOUNNI, Nor, MURPHY, Gillian, EDWARDS, Dylan R, FOIDART, Jean-Michel, NOËL, Agnès, PENNINGTON, Caroline J, ENGLISH, William R, VAN DEN BRULE, Frédéric, BLACHER, Silvia, GILLES, Christine, MUNAUT, Carine, MAQUOI, Erik, LOPEZ-OTIN, Carlos
• Format: Journal Article Web Resource
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2006; American Association for Cancer Research, Inc. (AACR)
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Growth Processes - physiology; Cell Line, Tumor; Gynecology. Andrology. Obstetrics; Human health sciences; Humans; Immunohistochemistry; Lung Neoplasms - enzymology; Lung Neoplasms - secondary; Lymphatic Metastasis; Mammary gland diseases; Matrix Metalloproteinases - biosynthesis; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Neoplasm Metastasis; Oncologie; Oncology; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Sciences de la santé humaine; Transfection; Tumors; Mammary gland diseases; Peptidases; Enzyme; Growth; Hydrolases; Metalloendopeptidases; Breast cancer; Malignant tumor; Metastasis
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.can-05-3012

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.