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Title: Effects of long-term tamoxifen treatment on ERa expression in breast cancer cells
Author: Bensmail, Abdelwahab
ISNI:       0000 0004 2747 7132
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2009
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Tamoxifen has long been the drug of choice in endocrine therapy of oestrogen receptor a ERa-positive breast cancer and still remains widely used due to its well-documented beneficial effect. However, its efficacy is often limited by the onset of acquired resistance and several clinical studies have suggested that a proportion of tumours, which are initially ERa-positive, lack the receptor at the time of tamoxifen relapse in the adjuvant or metastatic setting. The mechanisms underlying acquired ERa-negativity remain largely unknown and their elucidation is of therapeutic importance since breast cancer lacking ERa is associated with endocrine resistance, aggressive tumour biology and poor prognosis. This study addressed the issue of acquired ERa-negativity during tamoxifen therapy by assessing ERa expression in tamoxifen-resistant MCF-7-derived cells, which were cultured in the presence of the anti-hormone over a 30-month period. Results showed a progressive and significant reduction of total ERa mRNA and protein expression in response to tamoxifen therapy and this was accompanied with greatly increased aggressive tumour cell behaviour. The tamoxifen-treatment regimen also resulted in reduced expression of all ERa mRNA variants, which are generated through alternative promoter usage of the ERa gene. Such reduction was most apparent for ERa-mRNA variants C. Importantly, pharmacological modulation of cell signalling pathways identified the epidermal growth factor receptor EGFR signalling maintaining ERa levels, whilst c-Src kinase activity appeared to be the key underlying cause of ERa loss during tamoxifen therapy. Encouragingly, even after a 30-month treatment regime with tamoxifen, ERa loss was reversible with a c-Src inhibitor. The data presented in this thesis suggest that combinations of anti-hormones with c-Src inhibitors could retain ERa functions during tamoxifen therapy and prevent a drift towards more aggressive cancer cell behaviour.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available