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A Novel Somatic Mouse Model to Survey Tumorigenic Potential Applied to the Hedgehog Pathway

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts; ² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ³ Department of Pathology, Brigham and Women's Hospital; ⁴ Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ⁵ Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, Massachusetts

Requests for reprints: Andrew P. McMahon, Molecular and Cellular Biology, Harvard University, Biological Laboratories, Room 1059, 16 Divinity Avenue, Cambridge, MA 02138. Phone: 617-496-3757; E-mail: mcmahon{at}mcb.harvard.edu.

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)–related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice. (Cancer Res 2006; 66(20): 10171-7)

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