The Src homology phosphotyrosine phosphatase 2 (SHP2) promotes cell proliferation and survival signals induced by receptor Tyr kinases. More specifically, SHP2 is a requisite for EGFR and HER2 signaling pathways, receptors commonly dysregulated in breast and other cancers. In addition to the Ras-ERK and PI3K-Akt signaling pathways, SHP2 transduces ?-catenin signaling downstream of the EGFR and HER2. Therefore, SHP2 acts as a mediator and integrator of these pathways, which are generally regarded as separate. Moreover, our preliminary studies show that SHP2 is overexpressed in breast tumors, suggesting that its increased expression might enhance tumor growth. However, how SHP2 positively modulates the EGFR/HER2 and the ?-catenin signaling pathways is poorly understood. Thus, this research proposal addresses the under-explored, but important area in cancer. The central hypothesis is that SHP2-mediated synergy between the EGFR/HER2 and ?-catenin signaling pathways underlies the mechanism of SHP2 in promoting epithelial-to-mesenchymal transition (EMT) and cell transformation, leading to breast tumor development. This hypothesis is based on the following findings: i) SHP2 is a positive effector of mitogenic and cell survival signals, traits dysregulated in a cancer cell, ii) SHP2 integrates ?-catenin signaling with Ras and PI3K pathways, and iii) it is overexpressed in breast cancer.
The specific aims of this proposal are: 1) to explore the extent of SHP2 overexpression in breast cancer and elucidate the mechanism of action of SHP2 in HER2 signaling and transformation, 2) to study the molecular mechanism for EGFR/HER2-induced and SHP2-mediated ?-catenin activation and 3) to investigate the importance of SHP2 in HER2-induced tumorigenesis in vivo. SHP2 protein overexpression in primary breast tumors will be investigated by immunohistochemistry and immunofluorescence. The mechanism of action of SHP2 in HER2 and ?-catenin signaling will be investigated by site-directed mutagenesis, expression in appropriate cells and determining the effect of these expressions on signaling, cell growth and transformation. Finally, the importance of SHP2 in HER2-induced tumorigenesis will be studied in HER2 transgenic and SHP2 knockout (specifically in the mammary gland) mice.
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