Zebrafish and the discovery of cancer genes

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Jacqueline Lees, jalees@MIT.EDU, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E17-517B, Cambridge, MA 02139
We are using zebrafish to conduct large-scale screens for growth control and cancer genes. Nancy Hopkins' group has generated a collection of several hundred zebrafish lines that contain heterozygous mutations within genes that are essential for embryonic development. Since the vast majority of known mammalian tumor suppressors are required for embryonic viability, we hypothesized that this collection might include novel tumor suppressor genes. To test this notion, we have monitored the heterozygote mutant strains for evidence of reduced lifespan and externally visible tumors. To date, this screen has led to the identification of 8 different genes whose mutation renders the fish highly tumor-prone. Importantly, one of these genes is a zebrafish paralogue of a known mammalian tumor suppressor gene, validating zebrafish as a powerful genetic tool in the search for cancer genes. We are now using zebrafish and mouse models to understand how the encoded proteins inhibit tumor development.