Implications of the Activation of Matrix Metalloproteinase-2 (MMP-2) on the Metastasis in Breast Cancer

ABSTRACT

PURPOSE: The expression of matrix metalloproteinase-2 (MMP- 2) by cancer cells has been implicated in metastasis through cancer cell invasion of the basement membranes mediated by a degradation of collagen IV. However, the MMP-2 proenzyme requires proteolytic activation for its physiologic or pathologic role. We tried to 1) compare expression and activation of MMP-2 in breast cancers with benign tumors, 2) determine the correlation between the actviation of MMP-2 in breast cancer and established prognostic factors, 3) observe whether MMP-2 is expressed and activated in axillary lymph nodes as well, and 4) determine the degree of correlation between MMP-2 activity in lymph nodes and metastatic status, if MMP-2 is expressed in lymph node. METHODS: The specimens came from 11 fibroadenomas, 32 invasive ductal carcinoma and 129 axillary lymph nodes from cancer cases. Pro-MMP-2 cDNA transfected MDA-MB-231 cells were cultured and the conditioned media from them was used for a control. Zymography was used to monitor MMP-2 activation through the detection of the inactive proenzyme form (72 kDa) and the active form (62 kDa). Immunohistochemical staining was also performed for the localization of MMP-2 expression in tissues. RESULTS: 1) 72 kDa was expressed in all fibroadenomas and cancers, while 62 kDa was expressed in only 10 cases of fibroadenomas and all cancers. MMP-2 activity (62 kDa/72 kDa +62 kDa) was significantly higher in cancers than in fibroadenomas (P=0.014). 2) MMP-2 activity in cancers was significantly correlated with nodal metastasis (P=0.040). 3) The expression of MMP-2 in lymph nodes was very low and MMP-2 activity was not correlated with metastatic status. However, the immunohistochemical staining showed different staining patterns between the metastatic and non-metastatic nodes. CONCLUSION: We suggest that a measurement of the activation of MMP-2 could be useful as a prognostic marker representing metastatic potential in breast cancer. However, the low expression of MMP-2 in lymph nodes is an interesting subject for further study.