An elevated expression of membrane type-1
matrix metalloproteinase (MT1-MMP) is closely associated with multiple
malignancies. Recently, we discovered that recycled
MT1-MMP was trafficked along the
tubulin cytoskeleton into the centrosomal compartment and cleaved the integral centrosomal
protein pericentrin-2. These events correlated with the induction of
chromosome instability and
aneuploidy in nonmalignant Madine-Darby canine kidney cells. Accordingly, we hypothesized that
MT1-MMP is an oncogene that promotes malignant transformation of normal cells rather than just an
enzyme that supports growth of preexisting
tumors. To prove our hypothesis, we transfected normal 184B5 human mammary epithelial cells with
MT1-MMP (184B5-MT1 cells).
MT1-MMP was colocalized with
pericentrin in the centrosomal compartment and especially in the midbody of dividing cells. 184B5-MT1 cells acquired the ability to activate MMP-2, to cleave
pericentrin, and to invade the
Matrigel matrix. 184B5-MT1 cells exhibited
aneuploidy, and they were efficient in generating
tumors in the orthotopic xenograft model in immunodeficient mice. Because of the absence of
tumor angiogenesis and the resulting insufficient blood supply, the
tumors then regressed with significant accompanying
necrosis. Gene array studies confirmed a significant up-regulation of oncogenes and tumorigenic genes but not the angiogenesis-promoting genes in 184B5-MT1 cells. We believe that our data point to a novel function of
MT1-MMP in the initial stages of malignant transformation and to new and hitherto unknown transition mechanism from normalcy to
malignancy.