title: Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence.
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.
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201.
authors.forename: D W
authors.initials: DW
authors.lastname: Visscher
authors.forename: M
authors.initials: M
authors.lastname: Höyhtyä
authors.forename: S K
authors.initials: SK
authors.lastname: Ottosen
authors.forename: C M
authors.initials: CM
authors.lastname: Liang
authors.forename: F H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: J D
authors.initials: JD
authors.lastname: Crissman
authors.forename: R
authors.initials: R
authors.lastname: Fridman
mesh_terms: D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002278:Carcinoma in Situ / Q000201:enzymology* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2
chemical_list: D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; D011506:Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D008666:Metalloendopeptidases