The role of the Fer protein-tyrosine kinase in HER2-positive breast cancer
Loading...
Authors
Mullins, Graeme
Date
2015-07-31
Type
thesis
Language
eng
Keyword
Breast cancer , Fer kinase
Alternative Title
Abstract
Fer is a member of a distinct subclass of cytoplasmic protein-tyrosine kinases with homology to a family of adaptor proteins that regulate membrane-cytoskeletal remodeling events, including receptor endocytosis. Fer has been found to promote metastasis using shRNA knockdown and mouse engraftment models of lung cancer and triple-negative breast cancer. Interestingly, in a transgenic mouse model of HER2-positive breast cancer, mice targeted with a kinase-inactivating mutation (ferDR/DR) had delayed tumor onset, suggesting an important role for Fer activity in tumorigenesis. ferDR/DR mammary tumor epithelial cells (MTECs) from these tumors were hyper-sensitized to EGF stimulation, and this was linked to increased rates of EGFR internalization. This study identifies a role for Fer kinase activity in suppressing EGFR mitogenic signaling, as well as metastasis. In vitro experiments were conducted to validate that a rescue of Fer kinase activity in ferDR/DR MTECs suppresses EGF internalization. As this was correlated with a suppressive effect on downstream signaling and cell proliferation, this suggests that the native function of Fer is to negatively regulate transduction of EGFR signals. Next, MTECs were examined in vivo to show that Fer disruption impairs metastasis. When cells were examined in vitro, loss of Fer activity was associated with impaired cell migration and increased susceptibility to anoikis, suggesting that Fer contributes to multiple cellular processes during metastasis. Fer was also examined in a structure-function study by rescuing Fer expression in ferDR/DR MTEC cells using a panel of domain-specific mutants. We showed that Fer activity may be self-regulated by F-BAR domain activity and phosphorylation of Tyr402, as targeted mutations in these motifs impaired both Fer auto-phosphorylation and the ability of the kinase to suppress EGF-linked mitogenic signaling. Together, these results suggest that Fer plays a direct role in HER2-positive breast cancer by both promoting metastasis and by buffering signals originating from EGFR.
Description
Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2015-07-29 20:20:56.091
Citation
Publisher
License
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
Creative Commons - Attribution - CC BY
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
Creative Commons - Attribution - CC BY
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.