Carcinomas and 3 Matrix Metalloproteinases in Human Invasive Breast Expression and Tissue Localization of Membrane - Types 1 , 2 , Updated

Activation of the zymogen of matrix metalloprotelnase 2 (proMMP-2, progelatinase A) possibly is one ofthe key steps In Invasion and metastasis of various human carcinomas.Three differentmembrane-typeMMPS (MT-MMPs), MT1., MT2-, and MT3-MMPS are thought to be activators of proMMP-2Inthe tissues.MT4.MMPIsstructurallydifferentfromthe other three enzymes, sad Its function as proMMP-2 activator is uncertain. In thepresentstudyof humanInvasivebreastcarcinomas, weexamineda correlation between the expression of MT1-, MT2-, and MT3-MMPs, immunolocalizatlon of MT1. and MT2.MMPs, and proMMP.2 activation. Northern blot analysis demonstrated the predominant expression of MT1MMPmRNAIncarcinomatissues(20 of 20 cases),whereasMT2-MMP was detected In only 25% of the cases (5 of 20 cases), and no detectable expressionof MT3.MMPwas observed.The expressionlevels of MT1MMP but not MT2.MMP correlated well with the presence oflymph node and distant metastases, clinical stages, and size of tumors. Immunohisto chemically, 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 pres ence of these MT-MMPs. Activation of proMMP-2 was significantly higher in the carcinoma samples with lymph node or distant metastasis comparedto carcinomawithoutmetastasis,normalcontrol,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 activationof proMMP.2.