Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.726467
Title: Understanding epithelial to mesenchymal transition in human breast cancer
Author: Dubois-Marshall, Sylvie
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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Abstract:
Background and aims: Increasing evidence suggests that epithelial to mesenchymal transition (EMT) has a key role in breast cancer progression, underlying invasion, metastatic dissemination and acquisition of therapeutic resistance. However, this role is predominantly inferred from in vitro and animal studies and controversy regarding EMT in human cancer remains. This thesis has two principle aims. Firstly, to clarify the role of EMT in human breast cancer at the protein level. Secondly, to develop a three-dimensional in vitro assay to investigate cell invasion. Experimental Design: Two independent patient cohorts of high-grade, invasive ductal breast cancer were interrogated for their expression of key EMT proteins using quantitative immunofluorescence. This analysis was extended to paired lymph node metastases for a subset of cases. EMT-related cell lines were selected based on gene and protein expression data. These lines were investigated using lightmicroscopy, immunohistochemistry and immunofluorescence in a three-dimensional assay that models invasion across the basement membrane. Results: Two transcriptionally-driven EMT programmes were identified. One comprises vimentin, Snail and Slug and is uncoupled from E-cadherin downregulation. A second is characterised by up-regulation of WT1, Snail and Slug and down-regulation of E-cadherin. Importantly, acquisition of this phenotype in lymph node metastases predicts poor outcome. Some aspects of these programmes were recapitulated in vitro. Conclusions: These results suggest that EMT does occur in human breast cancer but in a manner distinct to that seen in vitro. The examination of primary tumours with their paired lymph node metastases may significantly contribute to understanding EMT. Lastly, in vitro models can reflect aspects of tumour biology and may prove invaluable in identifying clinically relevant, targetable pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.726467  DOI: Not available
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