Breast cancer is the most frequently diagnosed cancer in women with ~1.1 million worldwide cases. Despite intense study, in a significant fraction of women, tumor progression and disease relapse is inevitable underscoring a crucial gap in our understanding of these important hallmarks. Currently, little is known about the biochemical networks controlling these processes. The host lab has shown a fundamental role for the protein tyrosine phosphatase, SHP2, in tumor progression and metastasis in two aggressive breast cancer subtypes, human epidermal growth factor 2 (HER2) positive and triple negative breast cancer. Preliminary data in breast cancer cell lines revealed nuclear localization of SHP2 and proteomic analysis identified candidate nuclear substrates including nucleolin. However, whether a nuclear function of SHP2 and how SHP2 and its binding partners (i.e nucleolin) might impact breast cancer progression and metastasis remain unknown. This proposal will take advantage of original, state-of-the art technologies including multiphoton intravital imaging developed by the host laboratory to determine the nuclear function of SHP2 in normal mammary epithelial cells and during breast cancer progression and metastasis. Finally, it will validate nucleolin (and other identified candidates) as a SHP2 nuclear substrate and determine whether it is a critical downstream effector of SHP2 in breast cancer. Elucidation of the mechanisms driving tumor progression and metastasis is paramount for the development of novel therapeutic strategies.