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Mechanistic action of Death Associated Protein-3 (DAP-3) in breast cancer progression

Uherick, Michal 2021. Mechanistic action of Death Associated Protein-3 (DAP-3) in breast cancer progression. MD Thesis, Cardiff University.
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Abstract

Breast cancer is the most common cancer in the UK and places a substantial burden on health care systems. Despite advances in breast cancer treatments, it still causes substantial morbidity and mortality. Metastatic dissemination significantly influences patient outlooks, with the development of treatment resistance being a significant factor. This MD study aims to further explore the role of Death Associated Protein 3 (DAP-3) in breast cancer progression and therapy response and to shed light on the mechanisms of action involved in these processes. DAP-3 was targeted in MCF-7 and MDA-MD-231 breast cancer cell lines. Furthermore, potential interacting and mechanistic partners of DAP-3 were explored in clinical paired normal and breast cancer protein samples following immunoprecipitation with DAP-3 and protein micro-array analysis to identify differential expression patterns. This identified the Heat Shock Protein 90 (HSP90) molecule as a key player of a number of associated differential pathways. The relationship between DAP-3 and HSP90 was subsequently explored in in vitro functional tests utilising individual and collective DAP-3 knockdown and HSP90 inhibitor systems. This demonstrated DAP-3 KD reduced HSP90 expression, although HSP90 inhibition did not affect DAP-3 expression levels. In functional assays, DAP-3 knockdown led to nonsignificant increases in adhesion (MCF-7) and invasion (MDA-MD-231), and decreased migration (MDAMD-231). HSP90 inhibition showed a significant increase in adhesion (MCF-7), and a nonsignificant increase in growth (MDA-MD-231) and invasion (both cell lines). The combined effect of HSP90 inhibition and DAP-3 KD was inhibition of adhesion and invasion. Furthermore, the DAP-3-HSP90 relationship was assessed in clinical samples and suggest high levels of these molecules result in longer overall survival.

Item Type: Thesis (MD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 21 February 2022
Last Modified: 21 Feb 2022 10:36
URI: https://orca.cardiff.ac.uk/id/eprint/147679

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