Enhanced expression of tissue inhibitor of metalloproteinase‐2 (TIMP‐2) in the stroma of breast carcinomas correlates with tumor recurrence

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Abstract
The 72‐kDa (MMP‐2, gelatinase A) and the 92‐kDa (MMP‐9, gelatinase B) matrix metalloproteinases have been associated with tumor cell invasion and metastasis. Immunohistological staining of MMP‐2 and MMP‐9, basal lamina collagen IV and TIMP‐2 were performed on frozen sections of 83 invasive breast carcinomas. MMP‐2 and MMP‐9 were associated with neoplastic cell plasma membrane in 72% of cases and exhibited inter‐tumoral variability of staining intensity. MMP‐2 and MMP‐9 staining was not correlated with presence of metastases at time of diagnosis or with disease outcome. TIMP‐2 was detected in the peri‐tumoral stroma and was present in 87% of cases. Residual benign breast tissue was negative for TIMP‐2 staining. Neoplasms with diffuse TIMP‐2 staining (24%) recurred significantly more frequently (75% recurred) than cases with focal (42% recurred) or absent (27% recurred) TIMP‐2. Presence of collagen IV was negatively correlated with gelatinase staining. We conclude that up‐regulation of MMP‐2 and MMP‐9 expression in breast tumor cells is reciprocally correlated to collagen IV staining. Clinical outcome, however, is more closely related to the presence of TIMP‐2 than the corresponding MMPs. Enhanced TIMP‐2 expression, therefore, may denote a stromal response to tumor invasion, indicative of aggressive behavior in a subset of breast carcinomas.