Breast cancer (BC) ranks second among cancer deaths in women. Each year, this disease is diagnosed in over one million women worldwide. Although progress has been made, we still do not understand the biology of BC at a level that would explain why certain patients react well to therapy, whereas for others the disease is recurrent, with an inexorable downhill course. This proposal focuses on the role of SHP2 and other protein tyrosine phosphatase (PTP) in BC metastasis and comprises three parallel approaches. The first aim is to address the roles of SHP2 in metastatic spread. The second assesses the merits of SHP2 as a therapeutic target in established BC metastases and the third will screen for other PTPs involved in metastatic BC. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes, the protein tyrosine kinases (PTKs) and PTPs. Whereas the involvement of specific PTKs in BC has been well studied, the functions of specific PTPs in this disease are only now beginning to be elucidated. It has been discovered recently that SHP2 plays a fundamental role in tumor maintenance and progression in HER2-positive and triple-negative BCs, two subtypes associated with a poor prognosis. Importantly, SHP2 knockdown in established breast tumors blocked growth and reduced metastases. How does SHP2 knockdown in primary tumors reduce metastases? Can SHP2 inhibition in established metastases block their growth? Are other PTPs important for breast cancer metastases? To answer these questions, an intravital multiphoton microscope has been made for imaging fluorescently labeled metastatic BC cells expressing or lacking SHP2. These studies use state-of-the-art ex vivo and in vivo approaches to address the role of SHP2 and other PTPs in metastatic BC and should lead ultimately to the rational design of targeted therapies that will improve the clinical management of patients.