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Mechanisms of nuclear receptor resistance in prostate cancer

Doig, Craig L (2011)
Ph.D. thesis, University of Birmingham.

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Nuclear receptors (NRs) are essential transcription factors that participate in a diverse number of cellular functions. Many have attractive chemotherapeutic potential due to their ability to govern pathways of cellular differentiation, growth arrest and programmed cell death. There are numerous examples of NR signaling becoming disrupted in human malignancies including the prostate. Mechanisms that give rise to impaired receptor signalling are investigated herein, including pre-receptor regulation of NR ligand and epigenetically mediated hypoacetylation. Furthermore, attempts either to overcome or circumvent their disruption are investigated. In parallel to these one member of the NR subfamily was chosen for further analysis. The vitamin D receptor and its target gene CDKN1A were examined for recruitment of VDR, nuclear corepressor (NCOR1) and ppolymerase II to response elements. Using the non-malignant prostate epithelial cell line RWPE-1, and PC-3 prostate cancer cell line to represent stages of prostate disease progression the spatio-temporal binding characteristics in response to ligand were measured. These findings identified aberrant nuclear corepressor recruitment to the transcription start site of CDKN1A in malignant disease. In addition examination of coregulation of a microRNA known to target CDKN1A revealed a mechanism of NR sensitivity that is also perturbed in prostate cancer. MiR106b also showed elevated tumour and serum expression in prostate cancer, suggesting a new biomarker of VDR responsiveness.

Type of Work:Ph.D. thesis.
Supervisor(s):Campbell, Moray and McCabe, Chris
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3005
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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