Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells.
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.
Golubkov
Vladislav S
VS
Cancer Research Center, The Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Chekanov
Alexey V
AV
Savinov
Alexey Y
AY
Rozanov
Dmitri V
DV
Golubkova
Natalya V
NV
Strongin
Alex Y
AY
D000782:Aneuploidy; D000818:Animals; D001940:Breast / Q000201:enzymology* / Q000648:ultrastructure; D002460:Cell Line; D043171:Chromosomal Instability; D004847:Epithelial Cells / Q000201:enzymology / Q000648:ultrastructure; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics; D053511:Matrix Metalloproteinase 14 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis
D053511:Matrix Metalloproteinase 14