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PG12-34 Elliott Lay summary Principal Investigator: Professor David Elliott, Professor of Genetics at the Institute of Genetic Medicine, Newcastle University Lay title: How androgens drive prostate cancer cell growth What are you proposing? We aim to identify critical molecular ‘switches’ that regulate the growth of prostate cancer cells and determine their potential use in diagnosing aggressive disease. Androgens are steroid hormones which stimulate prostate cancer cells to grow. We have looked in detail at changes in gene expression of prostate cancer cells when treated with androgens and identified a number of key genes which show important changes. Some of the genes are working in overdrive in response to androgens, while others are being shut down. We want to uncover the molecular details of these changes to look at how they influence the progression of the prostate cancer, and whether or not they can be used to diagnose different types of disease. Why are you proposing it? While some prostate tumours are low grade and perhaps do not require further intervention, others can be more aggressive. It is currently difficult to identify different courses the disease might take in individual patients. Lowering androgen levels or stopping androgens from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time, but prostate tumours can switch to a more aggressive form in which cell growth and division take place without androgen stimulation. A recent study of breast cancer showed that it is actually 10 different diseases with genes going haywire in broadly 10 different ways, and each subtype of disease requiring a different treatment. The situation in prostate cancer may be similar. Identification of different growth mechanisms regulating androgen-dependent growth of prostate cancer cells will help define different types of prostate cancer, predict which cancers are likely to become aggressive, and have the potential to allow doctors to personalise a patient’s treatment based on the type of prostate cancer they have. How are you proposing to do it? Androgen steroid hormones drive prostate cancer progression by turning genes on and off, leading to expression of new proteins which stimulate cell growth and division. We recently globally identified genes that are regulated in response to androgens. We have now correlated these with genes known to be frequently mutated/miss-regulated in prostate tumours and used this to identify a group of genes which are involved in pathways with established roles in prostate cancer. These genes include a new version of the TSC2 tumour suppressor gene, which unexpectedly seems to drive prostate cell growth, a protein called PTPRR, and two proteins involved in PI3 kinase signalling. We want to test whether these genes are important molecular switches in prostate cancer. This will be achieved by “forcing” their expression and measuring cell growth, division and the activity of important signalling pathways within cells. We will then examine the expression of these proteins in prostate cancer tumours to see whether these proteins can be used to work out which cancers are more aggressive. Prostate Cancer UK is a registered charity in England and Wales (1005541) and in Scotland (SC039332). A company limited by guarantee registered number 2653887 (England and Wales). How long will it take? Three years What is the budget? £159,129 What are the expected outcomes? The expected outcome of the project will be the identification and characterisation of new androgen regulated target genes which drive prostate cancer development and pathology. We will also determine whether these genes have the potential to be used as biomarkers to diagnose different types of prostate cancer. How could it make a difference to the lives of men affected by prostate cancer? A greater understanding of the proteins and signalling pathways involved in prostate cancer cell growth will help decide which prostate cancers need to be treated, and improve treatment by tailoring drugs for a patient's exact type of disease. Please write a summary of the project in one sentence only. The identification of important androgen regulated genes involved in prostate cancer cell growth and progression with the aim of identifying new biomarkers to distinguish aggressive from indolent disease.