Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas.
Activation of the zymogen of matrix metalloproteinase 2 (proMMP-2, progelatinase A) possibly is one of the key steps in invasion and metastasis of various human carcinomas. Three different membrane-type MMPs (MT-MMPs), MT1-, MT2-, and MT3-MMPs are thought to be activators of proMMP-2 in the tissues. MT4-MMP is structurally different from the other three enzymes, and its function as proMMP-2 activator is uncertain. In the present study of human invasive breast carcinomas, we examined a correlation between the expression of MT1-, MT2-, and MT3-MMPs, immunolocalization of MT1- and MT2-MMPs, and proMMP-2 activation. Northern blot analysis demonstrated the predominant expression of MT1-MMP mRNA in carcinoma tissues (20 of 20 cases), whereas MT2-MMP was detected in only 25% of the cases (5 of 20 cases), and no detectable expression of MT3-MMP was observed. The expression levels of MT1-MMP but not MT2-MMP correlated well with the presence of lymph node and distant metastases, clinical stages, and size of tumors. Immunohistochemically, MT1-MMP was localized predominantly in the carcinoma cells in all of the samples (32 of 32 cases). Immunostaining of MT2-MMP in the carcinoma cells was observed in only 38% of the cases (12 of 32 cases). Immunoblot analysis of tumor homogenates confirmed the presence of these MT-MMPs. Activation of proMMP-2 was significantly higher in the carcinoma samples with lymph node or distant metastasis compared to carcinoma without metastasis, normal control, or fibrocystic disease (P < 0.05). An increase in the activation ratio of proMMP-2 correlated directly with the expression of MT1-MMP but not MT2-MMP, as measured by either Northern blot analysis or immunostaining. These results suggest that MT1-MMP may play a key role in human breast carcinoma invasion and metastasis by being predominantly responsible for activation of proMMP-2.
Ueno
H
H
Department of Molecular Immunology, School of Medicine, Kanazawa University, Ishikawa, Japan.
Nakamura
H
H
Inoue
M
M
Imai
K
K
Noguchi
M
M
Sato
H
H
Seiki
M
M
Okada
Y
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D017364:Collagenases / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism
D004792:Enzyme Precursors; D012333:RNA, Messenger; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1