The Role of Endocytic Adaptor Endophilin A2 in Human Breast Cancer Signaling, Metastasis, and Targeted Therapy
Loading...
Authors
Baldassarre, Tomas
Date
Type
thesis
Language
eng
Keyword
Breast cancer , Metastasis , Endophilin , Endocytosis , HER2 , Triple-Negative , Trastuzumab
Alternative Title
Abstract
The 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.
Description
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
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.
Attribution-NoDerivs 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
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.
Attribution-NoDerivs 3.0 United States