Molecular Mechanisms of Hormone-independence of Prostate Cancer

University Of Maryland Baltimore, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanisms of hormone refractory growth and metastasis of prostate cancer (PCA). We have shown previously that posttranslational modifications, including phosphorylation and ubiquitination, play an important role in regulation of transcriptional activity and specificity of the androgen receptor (AR) under androgen-depleted conditions. The precise mechanisms by which these posttranslational modifications regulate transcription program of AR in PCA cells remain largely unknown. Our preliminary study suggest that phosphorylation and ubiquitination modifications of AR may be coupled and coordinately regulate AR activity. In addition, we have identified several novel AR splicing variants lacking the ligand-binding domain in hormone-refractory PCA cells. One of the major splicing variants, AR3, is upregulated during PCA progression and its expression level predicts the risk of tumor recurrence. AR3 may play a distinct, yet essential, role in castration-resistant growth through regulating a unique set of genes which are not regulated by the prototype AR. This has added another layer of complexity of regulation of AR-mediated transcription program. To better understand the role of AR3 in PCA development and progression, we have, for the first time, established a transgenic mouse model AR3Tg by targeted overexpression of AR3 in prostate epithelium to recapitulate pathological changes occurred in human PCA. Our initial characterization of AR3Tg revealed that enforced-expression of AR3 in prostatic epithelial cells activates multiple growth factor signaling pathways and promotes proliferation in prostate epithelium compartment, leading to an increase of cells expressing stem/progenitor cell markers. We have also showed that AR3 is phosphorylated by multiple protein kinases as well as ubiquitinated. We will utilize this animal model to study how posttranslational modifications of AR3 modulate its activity. We propose to test the hypothesis that the transcriptional activity and specificity of AR and its splicing variant AR3 may be regulated co-ordinately by multiple posttranslational modifications which may lead to differential recruitment of co-factors to the regulatory regions of their target genes. Three specific aims are proposed: Aim 1, Test whether AR transcriptional activity is coordinately regulated by phosphorylation and ubiquitination under androgen-depleted conditions; Aim 2, Examine mechanisms by which AR3 activity is regulated; Aim 3, Examine the functional interaction between AR and AR3 under both normal and Pten-deficient background and its contribution to prostate cancer progression.