Prostate cancer ranks first in incidence and prevalence and second as a cause of cancer-related deaths among American men. American black men suffer the highest incidence of prostate cancer in the world. Although prostate cancer appears to develop via a multistep process, little is known about the molecular alterations involved in prostate carcinogenesis. One vital factor in prostate biology and the growth control of prostate cancer is the influence of androgens. Androgenic effects are mediated through the androgen-androgen receptor (AR) complex which acts as a transcription factor regulating the target genes. Androgen-independent tumor growth accounts for the rapid progression of prostate cancer following failure of primary androgen ablation therapy. Whether a change in the molecular mechanism of AR expression can contribute to the progression of human prostate cancer to an androgen- independent state is an important question and will be the major goal of this proposal. We have found sequences within the AR gene which could be the essential elements for control of AR expression in human prostate cancer. Hence, we have proposed several specific aims to test the following three hypotheses: Hypothesis I. Could we develop an assay based on these """"""""essential elements"""""""" to determine the hormone-responsive state of prostate cancer (androgen-dependent versus androgen-independent stages). Hypothesis II. Cis-acting elements in human AR minigene may decide the cell-specific expression of AR and the amount of trans-acting factor that bind to these cis-acting elements can also control AR-specific expression. If we can identify these cis-acting elements and trans-acting factors, we could then develop a therapeutic drug based on the above mechanisms to treat prostate cancer by preventing prostate cancer progression into androgen-independent stage. Hypothesis III. To understand more about prostate cancer etiology, we can use this mini-AR gene-ARECAT assay or cis-acting elements and/or trans- acting factors as tools to screen prostate tumors from (1) different age groups (2) different stages of prostate cancer; and (3) different races (Taiwanese/Japanese versus American white/black); (4) spontaneous prostate tumor from rats treated with different diet.
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