This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term objective of this project is to explore the potential of the Src homology phosphotyrosyl phosphatase 2 (SHP2) as a therapeutic target for the treatment of breast and other cancers characterized by overexpression of EGFR and HER2, while the current objective is to increase our understanding of SHP2 in EGFR/HER2 and ¿-catenin signaling. Therefore, the central hypothesis is that SHP2-mediated synergy between the EGFR/HER2 the ¿-catenin signaling pathways plays a major role in breast cancer development. To test this hypothesis, the following specific aims have been proposed: 1) study the molecular mechanism of SHP2 in transducing HER2 signaling and transformation and 2) investigate how SHP2 mediates ¿-catenin activation downstream of EGFR and HER2 and examine how this event translates into tumor development and epithelial-to-mesenchymal transition (EMT). To address these questions, we will employ site-directed mutagenesis of SHP2 target phosphorylation sites, expression in normal or cancerous breast cells and analysis of effect on signaling, cell transformation and in vivo tumor development. We will also use Si-RNA-mediated knockout of a-catenin to corroborate mutant expression studies; we have already developed the Si-RNA knockout system for SHP2. The relevance of this proposal is that it addresses unanswered questions in breast cancer with the potential to provide a new drug target.