breast cancer metastases. Phosphatases. SHP2
Sausgruber N, Coissieux M-M, Britschgi A, Wyckoff J, Aceto N, Leroy C, Stadler M B, Voshol H, Bonenfant D, Bentires-Alj M (2015), Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases., in Oncogene
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Bonapace Laura, Coissieux Marie-May, Wyckoff Jeffrey, Mertz Kirsten D, Varga Zsuzsanna, Junt Tobias, Bentires-Alj Mohamed (2014), Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis., in Nature
, 515(7525), 130-3.
Breast cancer ranks second among cancer deaths in women. Each year, this disease is diagnosed in over one million women worldwide and more than 400,000 lives are lost. Although progress has been made, we still do not understand the biology of breast cancer 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. Improved treatment options are urgently needed to end this stalemate. New therapies are likely to arise only from a more comprehensive understanding of the “wiring diagram” of breast cancer cells. This proposal focuses on the role of the protein tyrosine phosphatase (PTP) SHP2 in breast cancer metastasis and comprises two parallel approaches. The first aims to define the substrate(s) of SHP2 in breast cancer. The second addresses the roles of SHP2 in metastatic spread and assesses its merits as a therapeutic target in established breast cancer metastases.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. Not surprisingly, tyrosine phosphorylation has an important role in breast cancer. Whereas the involvement of specific PTKs in breast cancer, such as the HER2 receptor, has been well studied, the functions of specific PTPs in this disease are only now beginning to be elucidated. SHP2 is a ubiquitously expressed PTP that transduces mitogenic, prosurvival, cell fate and/or pro-migratory signals from almost all growth factor, cytokine and extracellular matrix receptors. It is required for the full activation of the ERK/MAPK pathway downstream of most receptors and has been shown to play a broad role in development, cell fate and tumorigenesis. We have discovered recently that SHP2 plays a fundamental role in tumor maintenance and progression in HER2-positive and triple-negative breast cancers, two subtypes associated with a poor prognosis. Knockdown of SHP2 prevented invasion in 3D cultures and eradicated breast tumor initiating cells (TICs) in vitro and in xenografts. Importantly, SHP2 knockdown in established breast tumors blocked growth and reduced metastases. Notably, these effects of SHP2 are dependent on the activation of the ERK pathway. These observations provoke further critical questions. What is/are the substrate(s) of SHP2 in breast cancer? How does SHP2 knockdown in primary tumors reduce metastases? Can SHP2 inhibition in established metastases block their growth? To answer these questions, we have set up unbiased phospho-proteomic approaches and established an intravital multiphoton microscope for imaging fluorescently labeled metastatic breast cancer cells expressing or lacking SHP2. These studies use state-of-the-art ex vivo and in vivo approaches to address the role of SHP2 in metastatic breast cancer and should lead ultimately to the rational design of targeted therapies that will improve the clinical management of patients.Our specific aims are:1- To identify the substrate(s) of SHP2 in breast cancer2- To determine the mechanism of action of SHP2 in metastasis3- To assess the effect of SHP2 knockdown in established breast cancer metastases.