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Breast cancer and oxidative stress

Afzal, Maryam 2009. Breast cancer and oxidative stress. PhD Thesis, Cardiff University.

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Endocrine and anti-EGFR strategies are used to treat breast cancer. Unfortunately, resistance can be acquired. Deciphering resistance mechanisms remains essential to design treatments for this adverse state. Oxidative stress is the cellular imbalance of pro-oxidants (promoting cell death) and antioxidants (facilitating cell survival and chemotherapy/radiotherapy resistance). However, it remains unexplored whether endocrine or anti-EGFR resistance also associates with altered redox balance. In this project, redox balance was examined using in vitro human resistant breast cancer models TAMR, FASR, X-MCF and NEW DUBS, comparing with responsive w/tMCF7 cells using microarray analysis, PCR, and TAC, ROS, or MTT assays. Pro-oxidant levels increased significantly in all resistant models but this did not impact adversely on growth. Significantly increased antioxidant levels were also observed in all resistant models, perhaps limiting pro-oxidant increases to maintain cell survival. Antioxidants were also significantly induced by antihormones in w/tMCF7 cells that may limit apoptosis with early treatment. Expression of 15 antioxidant genes increased in resistant cells spanning multiple resistant states. While gefitinib challenge revealed many antioxidant genes were EGFR/kinase signalling-regulated in TAMR cells, gefitinib and further signal transduction inhibitors (STIs) indicated total antioxidant capacity was not. Thus, additional genes/signalling probably drive increased antioxidants in resistant cells future deciphering and depletion of antioxidants could feasibly block cell survival in multiple resistant states. Several STIs further increased pro-oxidants in TAMR cells, indicating oxidative stress was also not EGFR/kinase-promoted since STIs also further increased antioxidant capacity, this may again limit pro-oxidant increases and hence apoptotic effect. Importantly, the thesis revealed resistant cells may be particularly sensitive to agents inducing excessive oxidative stress. Redox balance and feasibility of agents influencing redox remains complex. However, new findings and concepts emerging from this thesis are worthy of future exploration for potential treatments for resistance to endocrine/anti-EGFR agents.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
ISBN: 9781303189548
Date of First Compliant Deposit: 30 March 2016
Last Modified: 08 Jan 2020 04:45

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