Characterisation of the role of dual-specific MAP kinase phosphatases in androgen receptor action in prostate cancer development

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Mitogen-activated protein kinase (MAPK) pathways play an important role in tumour progression by phosphorylating key molecules in signalling cascades. A major determinant of their action is the dura-tion and magnitude of the kinase activity, which in turn is regulated by MAPK phosphatases. One example of MAPK phosphatases is the dual-specific phosphatase (DUSP) family, which is implicated in the development of many cancers, especially prostate cancer. Androgen receptor (AR), a ligandac-tivated transcription factor also plays an essential role in prostate cancer development. Its action is regulated by androgens, androgen antagonists and reversible phosphorylation events. The aim of the project is to determine how different mammalian DUSPs can alter AR phosphorylation and influence AR action in prostate cancer development and in anti-androgen resistance during prostate cancer therapy. The experimental approach to this study is to knock down the expression of the different DUSPs by siRNA technique and to determine the impact this would have on AR phosphorylation and gene regulatory networks at different stages of prostate tumour development. A further objective of this study is to determine mechanistically how knock-down of DUSP expression contributes to anti-androgen resistance in prostate cancer therapy. These studies will provide valuable information on which DUSP to target pharmacologically in the future treatment of prostate cancer.