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Matrix Metalloproteinases Play an Active Role in Wnt1-Induced Mammary Tumorigenesis

¹ Division of Hematology/Oncology, Department of Pediatrics; Departments of ² Molecular Microbiology and Immunology and ³ Biochemistry and Molecular Biology, USC Keck School of Medicine; and ⁴ The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California

Requests for reprints: Yves A. DeClerck, Division of Hematology/Oncology, Children's Hospital of Los Angeles, Mail Stop 54, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-669-2150; Fax: 323-664-9455; E-mail: declerck{at}usc.edu.

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. (Cancer Res 2006; 66(5): 2691-9)

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