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Title: The tumour suppressor P53 and apoptotic regulatory proteins in breast cancer survival and response to therapy
Author: Hinnis, Adel Rady
ISNI:       0000 0001 3578 9417
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2005
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Many breast cancer patients receive chemotherapy as part of their treatment, but unlike hormonal therapy there are no specific markers for predicting response. Almost all cancer therapies induce cell death by apoptosis. Therefore, factors that control apoptosis such as the tumour suppressor p53 and other regulatory proteins could provide important clues.;Initially breast cell lines (MCF-7, T47-D, ZR-75, MDA-MB-231, MDA-MB-468, HBL-100 and MBA-MB-436) were characterised with regard to proliferation, apoptosis, p53 and phosphorylated p53, p21waf-1, ChK2, bcl-2, bax, bcl-x, survivin and XIAP, using immunocytochemistry and western blotting. The cells apart from HBL-100 and MDA-MB-436, were then treated with different doses and durations of doxorubicin and paclitaxel. Proliferation was suppressed and apoptosis induced mainly in cells with wild type p53. P53 was induced after treatment in both ZR-75 and MCF-7 cells. Strong staining for bcl-2 was found in ZR-75 cells and was down regulated with treatment. Bcl-x was strongly expressed in MCF-7, T47-D and MDA-MB-468. p21 waf-1 was higher in MCF-7 and ZR-75 cells, and was markedly induced after treatment, and to a lesser extent in the other cells. Bax, Survivin and XIAP were detected in all cell lines with some variation. Bax expression increased after treatment, Survivin decreased except in ZR-75 and XIAP decreased in MCF-7.;Breast cancers from patients who had all died from the disease and who had received either neo-adjuvant therapy or adjuvant chemotherapy and/or hormone therapy were examined for the same markers using immunohistochemistry, and related to clinicopathological factors. High proliferation index, the presence of phosphorylated p53, low expression of bcl-2 and over-expression of Survivin were associated with shorter duration of survival, with Survivin expression being independent of other factors. The presence of Survivin and being grade III significantly correlated with shorter survival in patients who received combined adjuvant chemotherapy and hormonal therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available