Identifying functional drivers of epithelial-mesenchymal transition (EMT) in human breast cancer: the integrin/ILK axis
AffiliationSurgery (St Vincent's)
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Razan Wafai
Breast cancer is the leading cause of cancer in women worldwide, and over 90% of deaths caused by breast cancer are due to metastases, many of which are not responsive to current therapies. The ability for cells to acquire a metastatic phenotype includes epithelial mesenchymal transition (EMT), invoked as a critical component of the metastatic cascade. During the process of EMT, epithelial cells undergo a temporary conversion acquiring molecular and phenotypic changes that facilitate the loss of epithelial features, and the gain of mesenchymal phenotype. Such transformation promotes cancer cell migration and invasion. EMT is typically characterized as a loss of the epithelial cell adhesion proteins E-cadherin and cytokeratins, coupled with the gain of mesenchymal-associated molecules N-cadherin and vimentin. However, these proteins may not always be present in cancer systems. For example, one of the limitations in the use of vimentin as a prognostic marker in breast carcinomas is the likelihood that vimentin-positive cells may have migrated away from the primary mass, and become buried in the surrounding stroma, which is also vimentin-positive. Therefore, the identification of new markers which better represent EMT in breast carcinomas, and allow for a more specific detection of EMT-derived or EMT-prone breast cancer cells in the tumour vicinity, could have a dramatic impact on breast cancer prognosis. The work presented in this thesis describes a comprehensive characterization of two human breast cancer EMT model systems: the in vitro PMC42 cell system and the in vivo EDW-01 patient derived xenograft system. Specifically, the focus of this project was to perform a sequence of studies to assess the regulation of α2 and β1 integrin (ITGα2, ITGβ1), and ILK. The functional role of the integrin/ILK axis in the mesenchymal state, and in the epithelial-to-mesenchymal transition is explored and assessed.
Keywordsbreast cancer; epithelial mesenchymal transition (EMT); integrins; ILK; PMC42; EDW-01
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