Human breast cancer cells activate procollagenase-1 and invade type I collagen: invasion is inhibited by all-trans retinoic acid

Matrix metalloproteinases (MMPs) play an important role in tumor cell invas ion and metastasis. These processes require the dissolution of the basement membrane and invasion of the stromal matrix (ECM), and are mediated by MMP s. Consequently, MMP inhibitors may be attractive as new anticancer agents. To examine the potential contribution of collagenase-1 (MMP-1) in invasion of stromal matrix, we used the highly invasive and metastatic breast cance r cell line MDA-MB-231 as a model system. These cells express procollagenas e-1 constitutively and this expression can be repressed by all-trans retino ic acid. Invasion of these cells into a collagen type I matrix was assessed by scanning electron microscopy (SEM), and was quantitated with a computer program and confocal laser scanning microscopy (CLSM). We found that MDA-M B-231 cells freely invaded the collagen type 1 matrix, suggesting that thes e cells possess a mechanism for activating the latent collagenase-1. In con trast, down-regulation of collagenase-1 expression by all-trans retinoic ac id caused these cells to become less invasive. To confirm a role for collag enase-1 in mediating collagen type I invasion, assays were carried out in t he presence of FN-439, an inhibitor of collagenase-1 enzyme activity. We fo und that in the presence of the proteinase inhibitor, invasion of type I co llagen by MDA-MB-231 cells was also reduced. These results indicate that co llagenase-1 produced by the breast tumor cells may enhance stromal matrix d egradation by enabling the tumor cells to modulate their own invasive behav ior, and suggest that decreasing collagenase-1 levels may be effective in b reast cancer therapy.