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Title: An investigation into the role of the transcription factor ERG and its regulation of the members of the insulin-growth factor signalling pathway in prostate cancer
Author: Adamo, Patricia Maria
Awarding Body: University of the West of England, Bristol
Current Institution: University of the West of England, Bristol
Date of Award: 2013
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Recently the fusion gene TMPRSS2-ERG has been highlighted as a cancer-specific event in prostate carcinogenesis and is present in up to 800/0 of prostate carcinomas. Fusion a llows the androgen-driven TMPRSS2 promoter to control transcription of the oncogene, ERG, resulting in abhorrent ERG overexpression. In other cancer settings, ERG fusion genes are known to regulate members of the IGF signalling pathways and the IGF pathway has been highly implicated in prostate cancer development. The insulin-like growth factors and their binding proteins may provide good indicators of ERG status in prostate cancer and as they are secretory proteins they may act as easily accessible biomarkers. To address whether there is fun ctional relationship between ERG and the IGF pathway. expression profiltng of ERG, IGF·I, IGF binding proteins ( I to 6) and the tumour-suppressor protein , PTEN were carried in prostate cancer ce ll-lines. lnvestigation into ERG isoform expression was performed along with chromatin immunoprecipitation and dualluciferase assay to determine ERG's transcriptional action on the IOF targets. ERG knockdown and over expression and downstream effects on the IGF targets were also determined followed by ERG, IGF-f and fGFBP status in clinical samples. The androgen·dependent, fusion containing VCaP cell·line was the highest expresser of ERG and IGF-I was not found to be expressed in any of the cell-lines. ERG Isoform profiling revealed heterogeneous patteming across cell·lines, with LNCaP being a non·expresser. Chromatin immunoprecipitation detennined that ERG was able to bind to the promoters ofal! the target genes. Dual-Iuciferase promoter assay showed that ERO can directly regulate the transcription of IGFBP-3, IGFBP-5 and PTEN but not IGF-I. Here for the first time, I present evidence for the binding and regulation of the IGF binding proteins (lGFBP-3 and IGFBP-5), along with the tumour suppressor protein, PTEN by the transcription factor ERG. Full elucidation of the effect of ERG and ERG fusion genes on the IOF signalling pathway, in the prostate cancer scenario could lead to the development for novel biomarkers of prostate cancer progression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available