ANDROGEN RECEPTOR EXPRESSION AND FUNCTION IN PROSTATE CANCER

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Androgens play an important role in cancer development and progression. Androgens exert their effects through activation of the androgen receptor. Although androgen receptor expression is lost following androgen deprivation therapy that induces clinical remission in most patients, androgen-independent prostate cancers express levels of androgen- receptor protein similar to those found in androgen-dependent prostate cancer and benign hyperplasia. This observation suggests that the androgen receptor may be as important for growth regulation in androgen-independent prostate cancer as it is in androgen-dependent prostate cancer and benign hyperplasia. Since prostate cancer develops more frequently and is more aggressive in African Americans than in Caucasians and, if the androgen receptor is critical for the regulation of proliferation of prostate cancer,, the importance of the androgen receptor should be even more apparent in African American than in Caucasian prostatic tissues. Yet, few if any, studies of the androgen receptor include tissues from African Americans. We will test the hypothesis that changes in the expression and function of the androgen receptor are critical to the progression. of prostate cancer and that these changes may differ between Caucasian and African Americans. In Aim 1, we will use automated video image analysis to compare androgen receptor expression and tissue levels of potential activators of the androgen receptor in androgen dependent versus androgen-independent prostate cancer in Caucasian versus American Americans. In Aim 2, we will search for molecular alterations in the androgen receptor gene in these same research specimens and determine whether these changes affected androgen receptor expression. Point mutations in the androgen receptor will be screened for using denaturing gradient gel electrophoresis and single stranded conformational polymorphism. Transient co-transfection assays will determine the functional characteristics of the mutant androgen receptors. The lengths of the glutamine and glycine repeat regions of exon A will be determined by direct sequencing. In Aim 3, analysis of serial biopsies of prostate cancer from patients treated by castration will allow temporal comparison of androgen receptor protein expression, molecular changes in the androgen receptor and cellular proliferation Tissue from the time of onset of proliferation will be used to explore potential mechanisms of androgen receptor activation and expression of androgen-regulated genes developed in the androgen-dependent CWR22 human prostate cancer xenograft and the regenerating rat prostate in Projects 2 and 3, respectively.. Insights gained should allow a more complete understanding of the role of the androgen receptor in the development of androgen-independent prostate cancer.