Functional Analysis of Steroid hormone orphan receptor in hormone refractory prostate cancer

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Prostate specific antigen (PSA) has been widely recognized as a most reliable tumor marker. A recent report of immunohistochemistry has demonstrated the inverse correlation between PSA staining intensity and tumor grade in prostate cancer tissues. The molecular mechanism of this phenomenon has been as yet unknown. We elucidated that a nuclear orphan receptor, COUP-TFI and TR3 receptor, had key roles in the PSA expression of prostate cancer tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that TR3 stable transfectant of LNCaP prostate cancer cells expressed low PSA despite of stimulation of androgen. Also, COUP-TFI and TR3 receptor was expressed in human prostate cancer tissues and tended to diminish coincident with decreased PSA expression. Transient transfection analyses of PSA promoter showed that COUP-TFI or TR3 receptor repressed PSA transcription in a dose-dependent manner. In situ hybridization showed that TR3 mRNA more highly expressed in high-grade prostate cancer tissues. These findings suggest that highly expression of COUP-TFI or TR3 receptor might be attributed to decrease PSA intensity in high-grade prostate cancer tissue through suppressing the PSA transcription.