Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis.
The Wnt signaling transduction pathway plays a critical role in the pathogenesis of several murine and human epithelial cancers. Here, we have used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop spontaneous mammary adenocarcinoma, to examine whether matrix metalloproteinases (MMPs)--a family of extracellular proteases implicated in multiple steps of cancer progression--contributed to Wnt1-induced tumorigenesis. An analysis of the expression of several MMPs by RT-PCR and in situ hybridization revealed an increase in the expression of MMP-2, MMP-3, MMP-9, MMP-13, and MT1-MMP (MMP-14) in hyperplastic glands and in mammary tumors of MMTV-Wnt1 transgenic mice. Interestingly, whereas MMP-2, MMP-3, and MMP-9 were exclusively expressed by stromal cells in mammary tumors, MMP-13 and MT1-MMP were expressed by transformed epithelial cells in addition to the tumor stroma. To determine whether these MMPs contributed to tumorigenesis, MMTV-Wnt1 mice were crossed with transgenic mice overexpressing tissue inhibitor of metalloproteinase-2-a natural MMP inhibitor-in the mammary gland. In the double MMTV-Wnt1/tissue inhibitor of metalloproteinases-2 transgenic mice, we observed an increase in tumor latency and a 26.3% reduction in tumor formation. Furthermore, these tumors grew at a slower rate, exhibited an 18% decrease in proliferative rate, and a 12.2% increase in apoptotic rate of the tumor cells in association with a deficit in angiogenesis when compared with tumors from MMTV-Wnt1 mice. Thus, for the first time, the data provides evidence for the active role of MMPs in Wnt1-induced mammary tumorigenesis.
Blavier
Laurence
L
Division of Hematology/Oncology, Department of Pediatrics, USC Keck School of Medicine, Los Angeles, California, USA.
Lazaryev
Alisa
A
Dorey
Frederick
F
Shackleford
Gregory M
GM
DeClerck
Yves A
YA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D019076:Transgenes; D051155:Wnt1 Protein / Q000096:biosynthesis* / Q000235:genetics
D007527:Isoenzymes; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases