90% of all cancer deaths are due to the systemic dissemination of cancer cells and the formation of metastases. Epithelial cancers make up the vast majority of cancers, and the conversion of epithelial tumor cells to invasive, metastatic cancer cells is accompanied by a process reminiscent of epithelial-mesenchymal transition (EMT). Wnt signaling is found activated in a growing number of cancer types, with the concomitant aberrant expression of Wnt transcriptional targets. These targets play critical roles in cancer cell proliferation, survival, migration, EMT and metastasis. Importantly, the current model of Wnt signaling and its output, although complex, is oversimplified, and efficient drugs interfering with this pathway in a cancer cell-specific manner are still lacking. Hence, unraveling the regulation of ?-catenin?s transcriptional activities is a prerequisite to translate our knowledge of Wnt signaling into the development of innovative and efficient cancer therapy. We here propose to decipher the events/players that fine-tune ?-catenin?s transcriptional activity in mouse models of colorectal and breast cancer. In particular, we will delineate the contribution of the nuclear co-factors Bcl9, Bcl9L and Pygopus (Pygo) to ?-catenin-mediated transcriptional activation. These have been shown to assemble a ?chain of adaptors? that can help orchestrate ?-catenin?s transcriptional activity. The interaction domains between Bcl9/Bcl9L, Pygo, ?-catenin, TCF and other components of the chain of adaptors have been established in great detail, and mouse lines harboring knock-in alleles of mutated versions of ?-catenin, Bcl9/Bcl9L and Pygo with defective interaction sites are being established by the Basler group (Subproject A). These knock-in mouse mutants will be crossed to mouse models of colorectal cancer (Subproject B) and of breast cancer (Subproject C), and the effect of disturbed interactions between ?-catenin, Bcl9/Bcl9L and Pygo on tumor formation and malignant tumor progression will be determined. Furthermore, we plan to derive cell lines from the genetically modified mice for further mechanistic studies (Subprojects A and C). Finally, gene expression profiling analysis will define a generic gene expression signature of nuclear Wnt signaling in cancer cells acquiring mesenchymal and stem cell-like traits during malignant tumor progression. From these multi-layered experimental approaches we anticipate new insights into nuclear Wnt signaling. As one potential outcome, we envision to identify common denominators of nuclear Wnt signaling in cancer, in particular during EMT and tumor metastasis. The genetic experiments with mouse models will also provide proof-of-principle as to whether the regulation of ?-catenin-mediated transcriptional activity by the chain of adaptors may serve as a specific target for the development of innovative cancer therapy.