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Characterisation of Androgen Receptor Variants in Breast Cancer and the Development of Thieno[2,3-b] Pyridines as Novel Anti-Cancer Compounds

Alkheilewi, Mohammad (2019) Characterisation of Androgen Receptor Variants in Breast Cancer and the Development of Thieno[2,3-b] Pyridines as Novel Anti-Cancer Compounds. PhD thesis, University of Essex.

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Abstract

In Breast Cancer(BCa), steroid receptors play a key role in the progression of the majority tumours. Oestrogen Receptor-α (ERα), for example,drives the growth of approximately 70% of tumours and is therefore a useful therapeutic target for this disease.Interestingly, the Androgen Receptor (AR) is the most commonly expressed steroid receptor in normal breast tissue and appears to also playan important role in BCa. In ERα-positive disease the crosstalk between ERα and AR is inhibitory to tumour growth. Sequencing studies have identified the presence of AR mutations in BCa, however little is known about the role of these in disease progression. This study aimed to further characterise AR-ERα cross-talk and to analyse the effect of AR mutations upon receptor activity. Several mutations were found to affect receptor activity, but these did not affect AR-ERα cross-talk. AR signalling is also important in Prostate Cancer (PCa) and hence therapies often target this signalling axis. Although successful initially, these treatments invariably fail and the tumours progress to the aggressive castrate resistant stage of the disease. Thieno[2,3-b]pyridine derivatives have been previously demonstrated to be effective inhibitors in BCa. Here we expanded the research by investigating the efficacy of these compounds upon PCa. Using growth assays, flow-cytometry analysis, florescent imaging and cell tracking assays it was demonstrated that the compounds are potent inhibitors of PCa proliferation and motility. Importantly,the drugs were found to induce multi-nucleation, G2/M arrest and promote apoptosis. Further, a drug pull-down assay suggested that the compounds bind to multiple targets involved in, for example, cytoskeleton dynamics and p53 signaling. In conclusion, these compounds represent a novel therapeutic approach for PCaand further work to assess their efficacy is warranted.

Item Type: Thesis (PhD)
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Mohammad Alkheilewi
Date Deposited: 20 Aug 2019 16:07
Last Modified: 27 Aug 2019 15:46
URI: http://repository.essex.ac.uk/id/eprint/25189

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