Correlation of Tissue Inhibitor of Metalloproteinase-2 with Proliferative Activity and Patients' Survival in Breast Cancer

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous regulators of matrix metalloproteinases (MMPs). They are believed to possess several distinct cellular functions, particularly the contradictory activities of inhibiting MMPs and promoting tumor cell growth. Immunohistochemistry was performed to detect TIMP-2 protein in 136 infiltrative breast carcinomas. TIMP-2 protein was analyzed in parallel with clinicopathologic features (tumor size, histologic type, nuclear and histologic grade, stage), patients' overall survival and ER, PR, Ki-67, topo IIα, c-erbB-2, p53 and bcl-2 proteins. Statistical analysis was performed using univariate and multivariate models analysis. Immunoreactivity for TIMP-2 was observed in cancer cells and stromal fibroblasts in 106 (77.94%) and 104 (76.47%) of 136 cases, respectively. TIMP-2 protein expression in stromal fibroblasts showed a statistically significant inverse correlation with tumor size (P = .014). An inverse correlation was also observed between TIMP-2 epithelial immunoreactivity and nuclear and histologic grade (P = .036 and P = .007, respectively). TIMP-2 protein reactivity showed statistically significant positive associations with topo IIα and bcl-2 in stromal and cancer cells, respectively (P = .032 and P = .001, respectively). TIMP-2 protein expression in cancer and stromal cells was associated with better patients' overall survival (P = .002 and P = .038, respectively). When evaluated by the Cox's proportional hazard regression model, this association was further established, but only as far as TIMP-2 expression in tumor epithelium was concerned (P = .019). Our results support the multifunctional potential of TIMP-2 through its correlation on the one hand to a favorable outcome, due to its MMP inhibitory activity and on the other to topo IIα contributing to its growth factor activity.