Prostate cancer has become the most common solid cancer in older men. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer, there is no effective treatment available for patients with metastatic androgen-independent disease. The poor prognosis for androgen-independent advanced prostate cancer reflects in part the lack of knowledge about the tumor's basic biology. In particular, very little is known about the molecular mechanisms that trigger the conversion of an initially androgen-dependent cancer to androgen-independence. Our goal is to understand the role of a novel prostate epithelium-specific transcription factor, PDEF (Prostate Derived Ets Factor), a member of the Ets transcription factor/oncogene family in human prostate cancer. PDEF is expressed in the luminal epithelial cells of normal human prostate and preliminary results indicate that PDEF expression is elevated in cancerous portions of the prostate. PDEF acts independently of androgen as a strong transcriptional enhancer of the PSA and PSMA promoter, two diagnostic markers used for monitoring androgen-dependent and -independent prostate cancer. Activated MAP kinases drastically enhance PDEF mediated transcriptional activation. PDEF also interacts and cooperates with the androgen receptor in inducing expression of the PSA gene. Thus, our hypothesis is that PDEF bypasses or activates the androgen receptor and thereby contributes to the progression from an initially androgen-dependent prostate cancer to an androgen-independent cancer. We propose to determine the role of this novel member of the Ets family in prostate cancer formation and progression and the possibility to use this new factor as another diagnostic tool and as a potential therapeutic target. Thus, the specific aims are:
Specific Aim #1. Does PDEF play a crucial role in prostate cancer development or progression? Specific Aim #2. Is PDEF a critical regulator of prostate-specific PSA gene expression? Specific Aim #3. Can PDEF activity explain the conversion of prostate cancer cells to androgen-independence? Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes and due to the direct implication of several members of the Ets family in various human cancers, PDEF is expected to play a role in prostate epithelial cell transformation or prostate cancer progression.
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