Show simple item record

dc.contributor.authorBaldassarre, Tomas
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2017-07-04T19:11:29Z
dc.date.available2017-07-04T19:11:29Z
dc.identifier.urihttp://hdl.handle.net/1974/15924
dc.description.abstractThe leading cause of death in breast cancer is metastatic burden. Classification of breast cancer cases by molecular subtype reveals that those categorized as triple-negative (TNBC) and human epidermal growth factor receptor 2 overexpressing (HER2+) exhibit more invasive phenotypes, higher rates of metastasis, and worse survival. Tumour progression requires signaling via receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2, as well as invasion through the extracellular matrix (ECM) directed by membrane-type 1 matrix metalloprotease (MT1-MMP). Coordinated endocytosis of these receptors is essential for their cellular functions. Endophilin A2 (Endo II) is a Bin/Amphiphysin/Rvs (BAR) domain protein involved in endocytosis. Studies have identified Endo II as a substrate of Src kinase involved in establishing and maintaining a tumorigenic and metastatic phenotype in mice. However, the specific role of Endo II in human breast cancer progression remains unclear. This thesis investigated the role of Endo II in human TNBC and HER2+ cancer models. High Endo II expression was detected in TNBC and HER2+ subtypes, and was correlated with poor prognosis in human breast tumours. Stable knock-down (KD) of Endo II in several human TNBC and HER2+ cell lines resulted in defects in internalization and signaling by EGFR and HER2 in TNBC and HER2+ models, respectively. Cell migration and invasion in vitro were also reduced upon Endo II KD. In TNBC cells, Endo II KD suppressed ECM degradation by invadopodia, despite higher levels of MT1-MMP on the cell surface. Endo II KD also limited tumour growth and metastasis in mammary orthotopic tumor xenograft models. Lastly, HER2 internalization and the cytotoxicity of Trastuzumab and Trastuzumab Emtansine (T-DM1) were suppressed in Endo II KD HER2+ cells. These results identify Endo II as a positive regulator of both breast cancer metastasis, as well as the cytotoxic response to antibody-based therapy. Overall, this thesis provides a foundation for refined approaches to alter Endo II expression and function in high-risk patients, as a means to increase sensitivity and mitigate resistance to targeted therapies.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada*
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreement*
dc.rightsIntellectual Property Guidelines at Queen's University*
dc.rightsCopying and Preserving Your Thesis*
dc.rightsThis 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.*
dc.rightsAttribution-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nd/3.0/us/*
dc.subjectBreast canceren_US
dc.subjectMetastasisen_US
dc.subjectEndophilinen_US
dc.subjectEndocytosisen_US
dc.subjectHER2en_US
dc.subjectTriple-Negativeen_US
dc.subjectTrastuzumaben_US
dc.titleThe Role of Endocytic Adaptor Endophilin A2 in Human Breast Cancer Signaling, Metastasis, and Targeted Therapyen_US
dc.typethesisen_US
dc.description.degreeDoctor of Philosophyen_US
dc.contributor.supervisorCraig, Andrew W.en
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.termsChapter 3 is unpublished. Restriction to be lifted following publication.en_US
dc.embargo.liftdate2022-06-30T15:11:15Z
dc.embargo.liftdate2017-11-07


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
Except where otherwise noted, this item's license is described as Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada