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<p>Abstract</p> <p>Background</p> <p>C/EBPα is a transcription factor essential for terminal differentiation of several cell types. It has not known if C/EBPα protein is expressed and functions in the prostate gland.</p> <p>Methods</p> <p>The presence of C/EBPα in normal and cancerous prostate epithelium was examined by immunochemistry. Over expression of C/EBPα in LNCaP cells was conducted with retrovirus-mediated transduction. PSA expression was examined by RT-PCR and western blot and PSA promoter activity by luciferase reporter assay.</p> <p>Results</p> <p>In normal prostate C/EBPα was expressed in the basal layer of the epithelium. In prostate cancer C/EBPα was detected at low levels throughout the cancers and in advanced prostate cancer C/EBPα expression was associated with decreased expression of AR and PSA. Overexpression of C/EBPα inhibited epigenetically PSA expression and was accompanied by the loss of expression of AR. Transient increase of C/EBPα inhibited the PSA promoter/enhancer activity independently of expression of AR.</p> <p>Conclusion</p> <p>In LNCaP cells C/EBPα over expression inhibits expression of PSA by AR -dependent and independent mechanisms and by extinguishing AR expression provides a model for hormonal independent cell growth.</p>