Brf1 - a novel contributor to prostate cancer?
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
Prostate cancer is the most common cause of cancer and second most common cause of cancer death in men in UK. Currently the molecular mechanisms of PC initiation and progression are poorly understood and therefore, treatment options in advanced PC are limited. Recent laboratory work at the Beatson Institute for Cancer Research has shown Brf1 is overexpressed in early PC and this seems to have a knock on effect for other important genes involved in PC development. We hope that our research would provide invaluable evidence for the role of Brf1 in PC development leading to more accurate prognostic information and novel targeted therapies.
Technical Summary
Aims: Prostate cancer (PC) is the most common cause of cancer and second most common cause of cancer death in men in UK. Brf1 is a transcription factor that can transform cells when overexpressed. Its activity is counteracted by the tumour suppressor RB. Preliminary studies show that Brf1 levels increase at the earliest stages of human PC and that patients with the highest Brf1 levels have significantly worse survival prospects. Our aim is to determine whether Brf1 levels correlate with clinical parameters and have reliable prognostic significance. By using transgenic mouse models we aim to identify the role of Brf1 in the transformation of prostate cells.
Hypothesis: Overexpression of Brf1 is an important step in prostate carcinogenesis.
Objectives
1.) To show whether Brf1 levels are raised in PC specimens and to correlate its expression levels with clinical parameters including Gleason scores and survival outcome of PC patients.
2.) To explore the consequences of over-expression and heterozygous deletion of Brf1 in prostates of adult mice in transgenic mouse models.
Methodology
1.) Expand on TMAs pilot data showing expression of Brf1 in prostate cancer biopsy specimens via immunohistoechemical (IHC) techniques. TMA available through the prostate collaborative network PROMPT (including Cambridge, Glasgow and Newcastle) will be studied by IHC and data corroborated to clinical parameters including survival outcome to test for prognostic significance.
2.) To test whether Brf1 mRNA assay by PCR is a reliable and useful diagnostic test: Urine samples from men with locally advanced tumour or benign prostates following digital rectal examination will be collected and processed to isolate prostate enriched cell pellet. RT-PCR will be applied to test if robust data can be obtained.
3.) Transgenic mouse models with Brf1 deletion or overexpression to determine effect on prostate tumour development. Cohorts will be monitored to determine whether Brf1 overexpression in this tissue is sufficient to drive any of the changes associated with prostate carcinogenesis. Characterisation of mouse models will be rigorous and involve histological and IHC assessment as well as in vitro cell culture and functional assays.
Scientific and Medical opportunities: Preliminary data suggest Brf1 may be a reliable biomarker for the early changes of prostate carcinogenesis. Brf1 manipulation has the potential to be a translational target for novel small molecule inhibitors and aid our understanding of the mechanisms that underlie early disease progression in prostate cancer.
Hypothesis: Overexpression of Brf1 is an important step in prostate carcinogenesis.
Objectives
1.) To show whether Brf1 levels are raised in PC specimens and to correlate its expression levels with clinical parameters including Gleason scores and survival outcome of PC patients.
2.) To explore the consequences of over-expression and heterozygous deletion of Brf1 in prostates of adult mice in transgenic mouse models.
Methodology
1.) Expand on TMAs pilot data showing expression of Brf1 in prostate cancer biopsy specimens via immunohistoechemical (IHC) techniques. TMA available through the prostate collaborative network PROMPT (including Cambridge, Glasgow and Newcastle) will be studied by IHC and data corroborated to clinical parameters including survival outcome to test for prognostic significance.
2.) To test whether Brf1 mRNA assay by PCR is a reliable and useful diagnostic test: Urine samples from men with locally advanced tumour or benign prostates following digital rectal examination will be collected and processed to isolate prostate enriched cell pellet. RT-PCR will be applied to test if robust data can be obtained.
3.) Transgenic mouse models with Brf1 deletion or overexpression to determine effect on prostate tumour development. Cohorts will be monitored to determine whether Brf1 overexpression in this tissue is sufficient to drive any of the changes associated with prostate carcinogenesis. Characterisation of mouse models will be rigorous and involve histological and IHC assessment as well as in vitro cell culture and functional assays.
Scientific and Medical opportunities: Preliminary data suggest Brf1 may be a reliable biomarker for the early changes of prostate carcinogenesis. Brf1 manipulation has the potential to be a translational target for novel small molecule inhibitors and aid our understanding of the mechanisms that underlie early disease progression in prostate cancer.