PCA is a leading cause of cancer-related death in American men. Like other cancers, it develops in the background of diverse genetic and environmental factors. Multiple complex molecular events characterize PCA initiation, unregulated growth, invasion, and metastasis. Distinct sets of genes and proteins dictate progression of PCA. Our group has been involved in the gene expression profiling of PCA to identify novel clinical markers and therapeutic targets. Furthermore, we have begun to address hypotheses generated from such global screening efforts. Using DNA chip technology, we recently identified the C-terminal binding protein (CtBP), as being elevated in metastatic PCA. The CtBP family of proteins plays an important role in normal development and cancer growth. A number of functions and binding partners have been ascribed to CtBP making it an enigmatic molecule. To our knowledge, the expression level or biological role of CtBP has not been characterized in the context of PCA or metastasis. We predict that alterations in CtBP levels or cellular localization contribute to PCA progression and may be associated with poor clinical outcome. The aims for this proposal are to: (1) Characterize CtBP gene and protein levels in PCA and assess potential clinical utility of measuring these molecules; and (2) characterize the functional role of CtBP in metastatic PCA. The first aim will use prostate tissue extracts, as well as high-density tissue microarrays (tissue ¿chips¿) to investigate the expression and cellular localization of CtBP. Based on this data, clinical associations with PCA progression will be ascertained. The second aim attempts to establish a biological function for CtBP in PCA development. We will use overexpression and RNA interference (¿gene inhibition¿) systems to study CtBP in the context of PCA. Cell proliferation, adhesion, invasion, and gene profiles will be examined in prostate cell lines in which CtBP levels are experimentally altered. While effective surgical and radiation treatments exist for clinically localized PCA, once PCA spreads, it is essentially incurable and most men diagnosed with metastatic disease will succumb over a period of months to years. Since 1973, there has been no significant improvement in 5-year survival for men diagnosed initially with metastatic PCA (http://seer.cancer.gov). Our long-term goal is to characterize the function of genes identified in our PCA gene screening studies with the aim of developing novel therapeutic targets useful in the treatment of advanced PCA. Characterizing genes, such as CtBP, which may control cell growth, metastasis, or gene regulation of PCA will offer novel targets for therapeutic intervention. Inhibitors of CtBP protein-protein interactions have already been developed. By characterizing CtBP and its role in PCA, we hope to provide a strong rationale for the design and development of CtBP-specific inhibitors in the treatment of advanced PCA.