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Title: Evaluation of drug resistance markers in breast cancers : roles in stemness and epithelial-to-mesenchymal transitions
Author: Asaduzzaman, Muhammad
ISNI:       0000 0004 6495 7864
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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There is an urgent need to identify markers of diagnostic and prognostic significance that can help in the development of novel cancer therapeutics. The principal aim of the present study was to evaluate nicastrin and EP300 as potential markers associated with breast cancer drug resistance. Nicastrin is a component of γ-secretase, an intermembrane complex of four proteins with roles in proliferation, cell adhesion and tamoxifen resistance. EP300 is a histone acetyltransferase and a transcriptional activator of E-cadherin which has been shown to regulate epidermal-to-mesenchymal transition and doxorubicin resistance via escape from drug-induced senescence. Using breast cancer cellular models in which nicastrin had been modulated or γ-secretase activity impaired with an inhibitor, we have found an insignificant role of nicastrin in altering chemosensitivity to doxorubicin and paclitaxel. Similarly, we have used stably transfected breast cancer cell models in which EP300 was either over-expressed or down-regulated and a knocked-out EP300 colon carcinoma cell model. We have confirmed EP300 role in regulating E-cadherin levels in vitro, to alter paclitaxel sensitivity and the generation of drug resistance. Furthermore, EP300 silencing was associated with increased in vitro tumourigenicity and cancer stem cell-like properties, while its ectopic expression in mesenchymal breast cancer cells rescued the epithelial, differentiated, paclitaxel sensitive phenotype. Gene expression profiling identified down-stream EP300 targets associated with drug resistance, epithelial-to-mesenchymal transition and cancer stem cells including ABCG2, BCL2, TNFRSF11B and TGFB2. Finally, immunohistochemical analysis of patient samples revealed a strong correlation between co-expression of EP300 and E-cadherin, particularly in metaplastic breast cancer, a rare aggressive form of invasive breast cancer with histological evidence of epithelial-to-mesenchymal transition which has a poor clinical outcome. Taken together, this study highlights the role of EP300 in mediating paclitaxel resistance by apoptosis evasion, probably via up-regulation of Bcl-2, and its link to regulation of epithelial-to-mesenchymal transition and stemness.
Supervisor: Yagüe, Ernesto ; Coombes, Charles Sponsor: Commonwealth Scholarship Commission
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral