Preliminary experiments, Ets2 is essential for very early mouse development and that mutant forms of Ets transcription factors may/suggest suppress Ras transformation of normal cells. The applicant proposes to investigate the importance of the Ras pathway activation of Ets2 during mouse development by extending gene targeting. In addition, he will investigate the mechanism of the suppression and reversal of Ras induced cellular transformation by stable expression in cell lines of three different types of dominant Ets mutants which either inhibit Ets transcriptional function or specifically repress or activate Ets-dependent gene expression. It will further be determined if the transformed phenotypes of human breast, ovarian and prostate carcinoma cell lines can be reversed by stable expression of these Ets dominant mutants. Finally, the possible activation of Ets transcription factor activities in transganic mouse tumors will be evaluated. The applicant feels that these studies will provide important information on the role of Ets transcription factors during development and carcinogenesis and may lead to a strategy of intervention applicable to cancers caused by multiple types of non-nuclear oncogenes.
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