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Title: Evaluation of hormonal receptors in breast cancer drug therapy
Author: Arif, Khalid
ISNI:       0000 0004 5351 1357
Awarding Body: University of Lincoln
Current Institution: University of Lincoln
Date of Award: 2014
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Breast cancer is the most common type of cancer in women worldwide. Approximately two-thirds of breast cancers are oestrogen receptor positive (ER+), which are activated via oestrogen dependent and independent mechanisms. The pathogenic role of oestrogen in breast cancer is well established, thus, targeting ER becomes an essential target in breast cancer anti-hormonal therapy. Tamoxifen is the most important anti-hormonal therapeutic agent which has been used as the gold standard in the treatment of ER+ breast cancer patients. Tamoxifen acts by competing with oestrogen for binding to the ER and reduces the transcription of oestrogen dependent genes. However, approximately 30-50% of patients either fail to respond or eventually become resistant to tamoxifen via not fully elucidated mechanisms, resulting in a serious clinical challenge in breast cancer management. Also there is increasing evidence that cancers are driven by cancer stem cells which are characterised by their ability for self renewal and resistance to drug therapies. Therefore the aim of this study was to evaluate the role of oestrogen receptors in both de novo and acquired tamoxifen resistant breast cancer. Study the influence of stem cell factors and the embryonic stemness gene in both MDA-MB-231 and MCF7/Tmx breast cancer cell lines with respect to the hypothesis that anti-stem cell factor and silencing of the Nanog may restore sensitivity to tamoxifen and enhance cell apoptosis. Qualitative and quantitative assays showed significant expression of CD44, PgP, MRP1 and embryonic markers (Nanog, Oct3/4 and Sox2) in MDA-MB-231 and MCF7/Tmx cells. Independently, MDA-MB-231, MCF7/Tmx and parental MCF7/WT cells were treated with monoclonal anti-stem cell factor (ACSF) and interfered with Nanog short interference RNA (siRNA), then growth rate, drug accumulation and apoptosis were assessed in response to 4-hydroxtamoxifen (4-OHT). Quantitative analysis of the influx and efflux rate was performed using the Technetium (99mTc) sestamibi assay in response to blocking SCF. iv Results show a significant apoptosis enhancement after treatment with ASCF in both MDA-MB-231 and MCF/Tmx cells (P<0.005) and a significant increase in the influx rate of 99mTc-MIBI in MDA-MB-231 cells. Growth rate and apoptosis markers were assessed prior to and after the silencing of Nanog gene. Results show a significant increase in apoptosis and reduction in the growth rate in both MDA-MB-231 and MCF/Tmx cells (P<0.005). This study demonstrates that multi drug resistance is mainly a phenomenon of acquired tamoxifen resistance, but not de novo resistance. The inhibition of SCF could inhibit cell proliferation and significantly increases cell sensitivity to tamoxifen in MDA-MB-231 and acquired tamoxifen resistant cells MCF7/Tmx. This study identified a high expression of embryonic markers Nanog, Oct3/4 and Sox2 in both MDA-MB-231 and MCF7/Tmx cells and that the silencing of the Nanog gene reduces cell proliferation and increases apoptosis in MDA-MB-231 and MCF7/Tmx cells. In conclusion, the results suggest that the neutralisation of stem cell factor may play an important role in enhancing tamoxifen response in ER- cells and less in acquired tamoxifen resistant breast cancer cells, via enhancing drug accumulation. The positive association of the embryonic markers with negative (ER-) and acquired tamoxifen resistant breast cancer cells could be used as prognostic markers and the knockdown of these transcription markers could enhance the response to tamoxifen and could be used in the management of breast cancer.
Supervisor: Rea, Carol; El-Sheemy, Mohamed; Hussain, Issam Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: B100 Anatomy ; Physiology and Pathology ; C130 Cell Biology