Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.676598
Title: The role of β-catenin in prostate cancer tumourigenesis and treatment resistance
Author: Brzezinska, Elspeth Anne
ISNI:       0000 0004 5373 0162
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2015
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Abstract:
Prostate cancer is a significant health problem for men in the western world. Of particular concern are patients who present with aggressive, invasive and metastatic disease, and develop lethal castration-resistant prostate cancer (CRPC) following androgen deprivation therapy. The activation of Wnt/β-catenin signalling is a common event in patients with the poorest prognosis, and frequently associated with the loss of PTEN and activation of the PI3K/Akt signalling pathway. However, the molecular basis for the significant impact of these aberrations in prostate cancer remains unclear. By using pre-clinical transgenic in vivo models, we have demonstrated that β-catenin is a potent proto-oncogene that drives prostate cancer tumourigenesis. Concurrent heterozygous loss of Pten exacerbates β-catenin-driven tumour progression and decreases host survival, while tumours are most aggressive when Pten is deleted. By investigating differential gene and protein expression, we have characterised co-operation between β-catenin activation and Pten loss through a complex network of intrinsic and extrinsic molecular events. These drive survival, growth and proliferation signals, and modulate tumour-immune response interactions to evade anti-tumourigenic processes, resulting in aggressive prostate cancer. Furthermore, by examining novel in vivo models of β-catenin-driven CRPC, we have indicated that β-catenin may promote treatment-resistance through androgen receptor (AR) reprogramming. We propose a mechanism for β-catenin-driven CRPC that is independent of classical AR signalling, and mediated through significant upregulation of canonical and non-canonical Wnt pathway components, which may be effectively targeted by Wnt inhibition. In summary, this thesis highlights a number of potential biomarkers and molecular targets that may be exploited to develop new strategies to manage patients with aggressive prostate cancer, to improve prognosis and avoid progression to lethal castration-resistant disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.676598  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)
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