Molecular genetic analysis of colon cancers has established that Wnt signaling pathway is involved in early tumor development. The transcription factors that commute Wnt signals into changes in target gene expression are members of the Lymphoid Enhancer Facto/T Cell Factor (LEF/TCF) family. There are full-length activating, and truncated dominant negative forms of LEF/TCFs as well as alternatively spliced isoforms. Based on previous work and results from other laboratories the following hypotheses are proposed. First, the hypothesis that full-length, activating isoforms of TCFs predominate in colon cancer as compared to normal tissue will be tested by defining the expression patterns of TCFs in normal, adenoma and adenocarcinomas (Specific Aim 1). Second, experiments are proposed to test two different hypotheses for the mechanism underlying previously reported unique activities of TCF isoforms (Specific Aim 2). Wild type and mutant TCF proteins will be studied in DNA binding assays. Third, the hypothesis that TCF family members and isoforms carry unique target gene specificities to impart distinct effects in cancer will be tested by two different strategies that disrupt TCF function in colon cancer cells. Effects will be assessed by global expression profiles and cell growth and viability assays (Specific Aim 3). Collectively, the work proposed will address important unknowns about the role that TCF proteins play in directing Wnt signals toward cell transformation and cancer progression.
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