Suppressor of fused gene in Carcinogenesis

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DESCRIPTION (provided by applicant): Developmental pathways first discovered in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with a variety of human congenital anomalies. Many developmental genes continue to play a role in regulation of cell growth and differentiation after embryogenesis, and mutations in these genes can result in cancer in children and adults. My laboratory showed that activation of the hedgehog pathway in humans through mutation in the hedgehog receptor "patched' (PTCH) causes Gorlin syndrome, an autosomal dominant disorder characterized by basal cell carcinomas of the skin, medulloblastomas, rhabdomyosarcomas and birth defects. Furthermore, we showed that virtually all sporadic basal cell carcinomas and a minority of other types of tumors have mutations that activate the hedgehog pathway. Activation of this pathway in the mouse results in a phenotype similar to human Gorlin syndrome with exactly the same tumor types. In Drosophila a downstream member of the pathway "suppressor offusecf' (SUFU) has an inhibitory effect on hedgehog signaling. By analogy to other inhibitory members of this pathway, the vertebrate homolog of SUFU should function as a tumor suppressor. This hypothesis is substantiated by the finding of homozygous inactivation of SUFU in human medulloblastomas. Our preliminary data and data from other investigators suggest that SUFU may also play a role in regulation of the WNT pathway. The purpose of this study is to determine the role of SUFU in mammalian cancers that arise with activation of the hedgehog or WNT pathway. The specific aims of this study are to: 1. Characterize the morphologic and cancer phenotypes of an SUFU knockout mouse, 2. Determine the modifying effect of loss of SUFU on the phenotype of PTCH knockout mice, 3. Develop a mouse with inducible expression of SUFU in skin and determine the effect of SUFU overexpression on tumors in PTCH heterozygous mice, 4. Determine the modifying effect of SUFU on the phenotype of APC heterozygous mice, 5. Determine if polymorphisms in human SUFU modify the biologic behavior of basal cell carcinomas and the Gorlin syndrome phenotype.