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Title: Does BFR1, a component of the transcription factor (TFIIIB), have a role in prostate carcinogenesis?
Author: Slater, Sarah Jane
ISNI:       0000 0004 5917 2456
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2016
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Prostate cancer is the commonest cancer diagnosed in UK men and the second commonest cause of cancer mortality. There is an urgent need to improve our ability to differentiate indolent from aggressive disease to achieve optimal evidence-based treatment choices. Tumourigenesis involves deranged cellular proliferation, which in turn necessitates gene translation to drive protein synthesis. The transcription products of RNA polymerase III (Pol III) play a critical role in protein synthesis. TFIIB-related factor 1 (BRF1) is a vital transcription factor and functions as part of the Pol III transcription apparatus to mediate transcription of transfer RNAs (tRNAs). tRNAs). In this thesis, using a range of in vitro/ in vivo pre-clinical models and clinical resources, I have characterised the status of BRF1 in prostate cancer. Abnormal BRF1 expression has been previously suggested in small pilot studies in a number of tumour types. Our recent immunohistochemistry data showed evidence of upregulated BRF1 expression in clinical prostate tumours. I observed high levels of BRF1 expression in a comprehensive panel of human prostate cancer cell lines. To further examine the functional significance of BRF1 in prostate cancer, BRF1 expression was manipulated. Upon transient over-expression of BRF1, cell proliferation was upregulated in several prostate cancer cell lines. In contrast, when Brf1 expression was reduced, cell proliferation decreased, along with associated G2/M accumulation. To test the in vivo function of BRF1 in prostate carcinogenesis, a genetically engineered mouse model (GEMM) was developed with enhanced Brf1 expression in the prostate, namely Pten-Brf1, while Pten was deleted to recapitulate commonly observed activation of PTEN/AKT pathway in clinical prostate cancer. The Pten-Brf1 mice harboured enhanced growth of their prostate tumours, although they were histologically similar to prostate tumours driven by homozygous Pten deletion (or Pten-). Overall, Pten-Brf1 mice survived significantly shorter period than the control Pten- mice. In summary, my research conducted in this thesis highlights a potential role for BRF1 (as part of the Pol III transcriptional apparatus) in prostate carcinogenesis. Further research is therefore warranted to define its role as a cancer biomarker and as a novel target for therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)