Carcinoma of the prostate (CaP) is now the #1 cancer in men and its #2 killer. While the tumor marker prostate specific antigen (PSA) has revolutionized diagnosis and therapy, PSA has also defined CaP's most unique and pressing issues: the tendency of CaP to almost exclusively metastasize to bone giving an osteoblastic response, and the inevitability fact that this initially androgen sensitive cancer becomes independent and therefore progresses and kills. The Project is divided into three subprojects and a technical core. The first project seeks to learn more about the mechanisms of CaP cell """"""""trafficking"""""""" to bone in men before and after therapies. The approach will entail performing reverse transcriptase-polymerase chain reaction (RT-PCR) assays on bone marrow aspirates initially to PSA and then to several other prostate specific markers (e.g. PSM, hK2). This investigation will describe the phenomenology of CaP cells in bone over time an therapy, and provide insight into the mechanisms for these bone events. The second project seeks to learn in the laboratory more about the mechanisms of CaP-bone interactions. The approach will be to examine in vitro and in vivo the influence of several factors in CaP cells that may """"""""allow"""""""" CaP bone implantation, growth, and/or the unique osteoblastic response. The factors will be examined including Cathepsin K, PSA, hK2, PSAM, bone morphogenic proteins, and urokinase-type plasminogen activators. The third project seeks to learn more about the molecular mechanisms of androgen independent (AI) regulation of the PSA gene. The approach will be to characterize further the transcriptional binding sites unrelated to the androgen response elements on the PSA promoter, pursue further the mechanisms of ligand-independent activation of the androgen receptor (AR), and examine in more detail the protein AR and non-AR regulators. This information will help understand the process of AI.
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