Functional characterisation of GAGEC1: A potential diagnostic/therapeutic target for proliferative disorders of the prostate

Introduction: Proliferative disorders of the prostate, such as prostate cancer and benign prostate hyperplasia (BPH), represent two of the most common diseases affecting the ageing male. Age-related changes of the prostatic stroma are associated with growth and trans-differentiation of fibroblasts, processes that in turn lead to the development of hyperplasia (BPH) and support neoplastic transformation of premalignant epithelial cells and prostate cancer. Preliminary data have identified GAGEC1, an X-chromosome linked gene that is preferentially expressed in prostate, testis and female reproductive tissues and up-regulated in several types of carcinoma. Significantly, prostatic GAGEC1 appears to be expressed only in the stromal cell compartment and is up-regulated in prostate cancer and BPH tissue samples. Methodology: This project will investigate the physiological and pathophysiological function of GAGEC1 in the human prostate by addressing three main issues. Firstly, the localisation of GAGEC1 protein will be investigated using specific anti-GAGEC1 antibodies. These studies will be performed both at the subcellular and cellular level. The latter will be analysed using a panel of tissue samples including differently staged tumours and will identify any correlation between gene expression and cancer progression. Secondly, factors influencing GAGEC1 gene expression (e.g. different cytokines, growth factors and potential protein phosphorylation) will be investigated to better understand the regulatory mechanisms determining GAGEC1 gene expression. Finally, potential interacting partners will be investigated using the yeast two-hybrid interaction trap assay and identification of proteins that co- precipitate in GAGEC1-containing complexes. Overall Aim: This investigation will provide information about the prostatic function of GAGEC1 for use in future studies to design appropriate GAGEC1-based methodologies for therapeutic intervention and/or diagnosis of stromal tissue remodelling and progression of BPH and prostate cancer.