This proposal aims to determine the role of cyclin D1 and androgen receptor (AR) mutations in prostate cancer cellular growth. Prostate cancer is the most frequently diagnose cancer in men in the United States and the second leading cause of male cancer deaths. Androgen ablation therapy (AAT) results in 60-80% initial response rates. However, prostate cancer unresponsive to androgen ablation therapy subsequently emerges in the majority of patients resulting in short survival time. AR mutations are frequently associated with AAT resistant tumors. The androgen receptor is involved in both differentiation and proliferation as specific mutations in the AR can selectively effect either differentiation (AR insensitivity) or proliferation. Cyclin D1 is overexpressed in many different tumor types including prostate cancer, and is required for oncogene induced growth in many cell types. Cyclin D1 overexpression promotes cellular proliferation and inhibits differentiation. We have found that cyclin D1 inhibits AR activity associated with direct binding to the AR. Mutant ARs found in AAT-resistant prostate cancer are promiscuously activated by other steroid hormones and evade cyclin D1 repression.
The aims of these studies are to determine the mechanisms by which cyclin D1 regulates the function of wild type and mutant AR in prostate cancer cells and how the AR in turn regulates cyclin D1.
The aims of these studies are: 1). Determine how cyclin D1 regulates wild type and mutant AR. We have shown cyclin D1 binds and represses the AR. Cyclin D1 fails to repress the mutant AR found in androgen ablation therapy resistant prostate cancer. 2). Determine the role of cyclin D1 in ARwt function in vivo. As we have shown in vitro that cyclin D1 inhibits AR activity we will determine whether cyclin D1 inhibits nK-1 vivo using cyclin D1-/- mice and their litter mate controls. Mice castrated and treated with DHT will be subjected to microarray analysis for androgen responsive genes. This approach has been previously used by this laboratory to study estrogen responsive genes in these animals. 3). Determine the mechanisms by which ARwt and ARmuts regulate cyclin D1. We will determine the role of ARwt and ARmut regulating cyclin D1 abundance. An understanding of the molecular interaction between the cyclins and wild type and mutant AR may provide important new approaches to block autonomous growth in prostate cancer.
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