The role of β-catenin in prostate cancer tumourigenesis and treatment resistance

Brzezinska, Elspeth Anne (2015) The role of β-catenin in prostate cancer tumourigenesis and treatment resistance. PhD thesis, University of Glasgow.

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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.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Supported by funding from Cancer Research UK.
Keywords: Prostate cancer, β-catenin, Wnt, Pten, tumourigenesis, castration-resistant disease
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
Supervisor's Name: Leung, Professor Hing Y.
Date of Award: 2015
Depositing User: Mrs Elspeth Brzezinska
Unique ID: glathesis:2015-7019
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 18 Jan 2016 14:33
Last Modified: 12 Apr 2024 13:19
Thesis DOI: 10.5525/gla.thesis.7019

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