title: Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas.
abstract: Collagenase-3 (matrix metalloproteinase 13; MMP-13), a protease originally identified in breast carcinoma, is characterized by a potent degrading activity against a wide spectrum of extracellular matrix proteins. The aims of this study were to localize and identify the MMP-13-expressing cells in invasive human breast carcinoma and to evaluate the role of MMP-13 in transition to invasive lesions by studying ductal carcinoma in situ (DCIS). We found expression of MMP-13 in stromal fibroblast-like cells in all 21 invasive ductal carcinomas studied and in 4 of 9 invasive lobular carcinomas. In most carcinomas, expression of MMP-13 was limited to small stromal foci in the tumor area. Combined in situ hybridization and immunohistochemistry showed coexpression of alpha-smooth muscle actin immunoreactivity and MMP-13 mRNA in myofibroblasts. In contrast, cytokeratin-positive cancer cells, alpha-smooth muscle actin-positive vascular smooth muscle cells, CD68-positive macrophages, and CD31-positive endothelial cells were all MMP-13 mRNA negative. In situ hybridization for MMP-13 in 17 DCIS lesions revealed expression in 10 cases. Immunohistochemical analysis of all DCIS cases identified microinvasion in 8 of the 17 lesions. Seven of the eight lesions with microinvasion were MMP-13 positive. Further analysis showed that MMP-13 expression was often associated with the microinvasive events. This particular expression pattern was unique for MMP-13 among other MMPs analyzed, including MMP-2, -11, and -14. We conclude that MMP-13 is primarily expressed by myofibroblasts in human breast carcinoma and that expression in DCIS lesions often is associated with microinvasive events. On the basis of these data, we propose that MMP-13 may play an essential role during transition of DCIS lesions to invasive ductal carcinomas.
authors.affiliation: Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark. schnack@finsenlab.dk
authors.forename: B S
authors.initials: BS
authors.lastname: Nielsen
authors.forename: F
authors.initials: F
authors.lastname: Rank
authors.forename: J M
authors.initials: JM
authors.lastname: López
authors.forename: M
authors.initials: M
authors.lastname: Balbin
authors.forename: F
authors.initials: F
authors.lastname: Vizoso
authors.forename: L R
authors.initials: LR
authors.lastname: Lund
authors.forename: K
authors.initials: K
authors.lastname: Danø
authors.forename: C
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002278:Carcinoma in Situ / Q000201:enzymology* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000201:enzymology* / Q000473:pathology; D017364:Collagenases / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D053509:Matrix Metalloproteinase 13; D009361:Neoplasm Invasiveness
chemical_list: D014408:Biomarkers, Tumor; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13