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Effects of the phosphatase SHP2 in breast cancer and metastasis

Sausgruber, Nina. Effects of the phosphatase SHP2 in breast cancer and metastasis. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10430

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Abstract

Breast cancer is the most frequent cancer in women and the most common cause of cancer related deaths in females. 90% of all cancer related deaths are due to metastatic spread to distant organs. In cancer, signaling pathways controlling proliferation, survival and migration are frequently deregulated. Tyrosine phosphorylation, controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), plays an important role in cell signaling. While the role of PTKs in cancer pathogenesis has been extensively studied over the past 30 years, the role of specific PTPs is less defined. We therefore studied the effects of the Src homology 2 domain containing phosphatase 2 (SHP2) in breast cancer. SHP2, encoded by PTPN11, is the first identified bona fide PTP proto-oncogene. It is a ubiquitously expressed phosphatase that acts as a signal enhancer downstream of growth factor, cytokine, and extracellular matrix receptors.
In the present study, we found an SHP2-dependent positive feedback loop that enhances the propagation of tumor initiating cells and the maintenance of breast tumors. We show that SHP2 is important for proliferation, loss of cell polarity, and invasion in a 3D culture model of invasive breast cancer. SHP2 promotes the progression from in situ to invasive carcinoma in vivo and is required for the maintenance and tumor-seeding ability of tumor initiating cells. We further demonstrate that knockdown of SHP2 in different breast cancer cell lines blocks tumor growth in vivo. Mechanistically, SHP2 promoted ERK1/2 activation leading to the upregulation of the transcription factors c-Myc and ZEB1. Increased expression of c-Myc led to upregulation of LIN28B which in turn repressed let-7 miRNA leading to overexpression of let-7 targets, including RAS and c�Myc. SHP2 also increased the expression of ZEB1, a transcription factor important in Epithelial-Mesenchymal Transition (EMT). Knockdown of SHP2 decreased the expression of the EMT markers fibronectin, vimentin and N-cadherin and reduced the metastatic load in a HER2-positive cell line.
We then assessed the effects of SHP2 on tumor cell motility, invasion and dissemination; all of which are characteristics crucial for metastasis formation. We found SHP2 to be important for cell migration, chemotaxis, and invasion in vitro and also for tumor cell motility and dissemination in vivo, suggesting a role for SHP2 in the early steps of metastasis. In an unbiased proteomics screen, we found that SHP2 activates several Src family kinases to induce migration and invasion. Depletion of SHP2 led to inactivation of c-Src and several Src substrates and blocked cell migration and invasion in vitro and in vivo.
SHP2 was recently suggested to have nuclear functions. We explored the mechanism of its nuclear import and its nuclear roles in different breast cancer models. We confirmed nuclear localization of SHP2 in several breast cancer cell lines and identified a nuclear localization signal facilitating the nuclear import of SHP2. Future studies will be necessary to fully understand the nuclear functions of SHP2 in breast cancer.
In summary, we identified and validated SHP2 as a target in breast cancer. We identified its downstream effectors, which mediate its pro-migratory invasive effects and started the exploration of its nuclear functions. Future studies should address the effects of pharmacological inhibition of SHP2 in breast cancer, provided the availability of selective SHP2 inhibitors. In addition, assessment of the effects of nuclear SHP2 in breast cancer is warranted.
Advisors:Hynes, Nancy
Committee Members:Bentires-Alj, Mohamed and Christofori, Gerhard
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
Item Type:Thesis
Thesis no:10430
Bibsysno:Link to catalogue
Number of Pages:197 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:15 Jul 2013 13:19

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