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Title: Drug sensitivity and apoptosis in tamoxifen resistant breast cancer
Author: Drayton, Ross
ISNI:       0000 0004 2750 8808
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Tamoxifen has long been used in the treatment of hormone responsive breast cancer. However, tumours frequently develop resistance within 2-5 years of treatment, characterised by the return of tumour growth. The epidermal growth factor receptor EGFR is an important contributing factor in allowing formerly tamoxifen sensitive tumours to grow in the presence of tamoxifen. High levels of EGFR in many tumours correlate with a poor prognosis and an increased resistance to cytotoxic drugs. It was the initial aim of this study to ascertain whether the increased EGFR signalling associated with tamoxifen resistance results in a phenotype more resistant to cytotoxic drugs, and to study the underlying mechanisms that may cause this. Rather than observing the expected increase in resistance to cytotoxic drugs upon the development of tamoxifen resistance, a greatly increased sensitivity to the radiomimetic drug bleomycin was observed. Inhibition of EGFR in either the tamoxifen sensitive or resistant cells had very little effect on bleomycin sensitivity, The rate of uptake of various drugs was measured, and found to be identical between tamoxifen sensitive cells and their tamoxifen resistant derivatives. Microarray analysis of mRNA levels of drug efflux proteins also showed no significant decrease in drug efflux pump gene expression, with two efflux pump genes MRP3 and MRP4 showing increased expression. Tamoxifen resistant cells displayed greatly increased sensitivity to the apoptosis inducer camptothecin, and showed a significant increase in the levels of activated caspases present. Immunocytochemistry revealed a significant downregulation of the anti-apoptotic protein bcl-2.. Sensitivity to bleomycin was also measured and was found to inversely correlate to bcl-2 status. Finally bcl-2 levels were modulated using oestrogens and antioestrogens, and with an siRNA directed against the oestrogen receptor. The effect on bleomycin sensitivity was examined. Reduction of bcl-2 expression by either method had no effect on bleomycin sensitivity
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available