The enhanced process of proteolysis of both the basement membrane and the stromal extracelluar matrix (ECM) contributes to the escape of breast cancer cells into the neighboring tissues, eventually leading to the formation of distant metastases. A group of enzymes thought to play a role in tumor cell invasion are the matrix metalloproteinases (MMPs). Much attention has been focused on MMP-2 and MMP-9, which are 2 members of the MMP family active against collagen of the basement membrane. The enzymatic activities of MMP-2 and MMP-9 are inhibited by the tissue inhibitors of metalloproteinases (TIMPs). TIMP-2, one member of TIMPs, inhibits MMP-2 and MMP-9. The imbalance between TIMPs and MMPs permits to tumor invasion and metastasis. Theretore, TIMPs constitute promising targets in the developmemt of anticancer terapies. Immunohistological stainings of MMP-2, MMP-9 and TIMP-2 were performed on paraffin-embedded tissue sections of 31 invasive breast carcinomas. MMP-2 and MMP-9 were associated with neoplastic cell cytoplasms in 65% of the cases and exhibited inter-tumoral variability of the staining intensity. The MMP-2 and MMP-9 stainings did not correlate with presence of metastases at time of diagnosis. TIMP-2 was detected in the peri-tumoral stroma and was present in 81% of the cases. Residual benign breast tissue was negative for TIMP-2 staining. Neoplasms with diffuse TIMP-2 staining (32%) have metastasis significantly more frequently (50% metastasis) than ceses with focal (20% metastasis) or absent (0% metastasis) TIMP-2. We conclude that the clinical outcome such as metastasis 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 the subset breast carcinoma.
Basement Membrane ; Breast Neoplasms* ; Breast* ; Collagen ; Cytoplasm ; Diagnosis ; Humans ; Matrix Metalloproteinases ; Metalloproteases ; Neoplasm Metastasis ; Proteolysis ; Tissue Inhibitor of Metalloproteinase-2 ; United Nations