Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases.
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.
Chabottaux
Vincent
V
Laboratory of Tumor and Development Biology, Centre de Recherche en Cancérologie Expérimentale, Center for Biomedical Integrative Genoproteomics, University of Liège, Belgium.
Sounni
Nor Eddine
NE
Pennington
Caroline J
CJ
English
William R
WR
van den Brûle
Frédéric
F
Blacher
Silvia
S
Gilles
Christine
C
Munaut
Carine
C
Maquoi
Erik
E
Lopez-Otin
Carlos
C
Murphy
Gillian
G
Edwards
Dylan R
DR
Foidart
Jean-Michel
JM
Noël
Agnès
A
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D008207:Lymphatic Metastasis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated