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Title: The role of apoptosis genes in breast cancer, with a focus on death associated proteins [DAP] and associated regulatory proteins
Author: Wazir, Umar
ISNI:       0000 0004 8502 9047
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2018
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Background: Death-associated protein 1 (DAP1) has recently been implicated in the control of autophagy. Death-associated protein 3 (DAP3) is an important component of the external apoptosis pathway. However, the roles of DAP1 and 3 in breast carcinogenesis have been overlooked in the recent literature. We intend to explore the role of DAP1 and DAP3 in human breast cancer. Methods: I studied the associations of mRNA expression levels of DAP1 and DAP3 with clinicopathological parameters of human breast cancer in a patient cohort (n=127). Furthermore, we established knocked-down sub-lines of MCF7 and MDA-MB-231, in which we studied the effects of knock-down of DAP1 and DAP3 on cell growth, adhesion, migration and invasion, as well as the expression of molecules related to apoptosis (caspase 8, caspase 9, IPS1 and DELE) and the cell cycle (p21WAF1 and cyclin Dl). Results: No association was found between DAP1 expression and clinical parameters in the clinical cohort (p=0.12). However, knockdown of DAP1 expression resulted in increased cell growth after an initial delay in MCF7 (on Day 3, 100 vs. 18.2; p=0.029; no difference at Day 5), as well as increased adhesion and migration in MDA-MB-231. In addition, there was reduced expression of caspase 8, and p21WAF1 in MCF7DAPlkd and IPS1 in MDA-MB-231DAPlkd. In the case of DAP3, decreased expression was associated with tumour grade in the clinical cohort (p=0.0034). Whilst knockdown resulted in reduced growth in both cell lines, it also was associated with increased adhesion, invasion and migration in MDA-MB-231. Conclusions: My data show some evidence for a role for DAP1 and DAP3 in breast cancer, further underlining the role of programmed cell death in carcinogenesis. A better understanding of the interactions of these molecules with other pathways relevant to carcinogenesis could further our understanding of apoptosis and autophagy, and their role in breast carcinogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available