MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival

Crucial event in the metastasis of cancer cells is the secretion of matrix metalloproteinases (MMPs), which are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-2 (MMP-2) is a gelatinase, which degrades basement membrane type-IV collagen. Immunohistochemistry was performed to detect MMP-2 protein in 135 infiltrative breast carcinomas. MMP-2 was studied along with clinicopathological parameters (tumor size, histological type, nuclear and histological grade, stage, lymph node status, ER, and PR), patients' survival and tissue inhibitor metalloproteinase-2 (TIMP-2), Ki-67, and p53 proteins. MMP-2 immunoreactivity was detected in the cytoplasm in cancer cells in 102 (75.6%) and in both tumor and tumor stromal cells in 37 (27.4%) of 135 cases respectively. MMP-2 reactivity in cancer cells displayed a statistically significant association with tumor size > 2 cm (p = 0.022). In tumor stromal cells a strong parallel association was observed between the expression of MMP-2 and TIMP-2 (p = 0.015), while an inverse correlation was found between MMP-2 and both Ki-67 and p53 (p = 0.033 and p = 0.034 respectively). In the subgroup with negative lymph nodes MMP-2 was also inversely associated with p53 in cancer cells (p = 0.045). Finally a statistically significant association was revealed using Kaplan-Meier and Cox's proportional hazard regression model between the MMP-2/TIMP-2 phenotype and patients' better survival (p = 0.021). Our results point out the strong relation between MMP-2 and TIMP-2 and the effect of the MMP-2/TIMP-2 phenotype in the patients' overall survival. The inverse correlation between MMP-2 and both Ki-67 and p53 can be explained by the potential inhibition of MMP-2 by TIMP-2. These results suggest the necessity of further investigation.