Matrix metalloproteinases (
MMPs) play an important role in
tumor cell invasion and
metastasis. These processes require the dissolution of the basement membrane and invasion of the stromal matrix (ECM), and are mediated by
MMPs. 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 cancer cell line MDA-MB-231 as a model system. These cells express procollagenase-1 constitutively and this expression can be repressed by
all-trans retinoic 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-MB-231 cells freely invaded the
collagen type I matrix, suggesting that these cells possess a mechanism for activating the latent
collagenase-1. In contrast, down-regulation of
collagenase-1 expression by
all-trans retinoic acid caused these cells to become less invasive. To confirm a role for
collagenase-1 in mediating
collagen type I invasion, assays were carried out in the presence of
FN-439, an inhibitor of
collagenase-1 enzyme activity. We found that in the presence of the
proteinase inhibitor, invasion of
type I collagen by MDA-MB-231 cells was also reduced. These results indicate that
collagenase-1 produced by the
breast tumor cells may enhance stromal matrix degradation by enabling the
tumor cells to modulate their own invasive behavior, and suggest that decreasing
collagenase-1 levels may be effective in
breast cancer therapy.