The long range objectives of this investigation are 1) to elucidate the mechanisms by which specific steroid receptor proteins are hormonally regulated in the adult prostate gland, 2) to determine the neonatal and prepubertal hormone imprints of the adult prostate, and 3) to elucidate the relationship between imprinting, steroid receptor levels, and tissue functionality during adult life. This proposal focuses on the relationships among androgen, estrogen and progesterone receptors (AR, ER and PR) within the separate ventral, dorsal and lateral lobes of the adult rat prostate.
The specific aims are 1) to determine if ER and PR are present within the three prostate lobes; to characterize their properties by saturation binding analysis, immunoassays, sucrose gradient analysis and positive verification with monoclonal antibodies; and to identify and quantitate their mRNA levels by hybridization with cDNA; 2) to test the functionality of ER and PR by observing their ability to bind with high affinity to nuclear components following ligand administration, and, for ER, to induce synthesis of specific proteins such as PR; 3) to determine the hormonal regulation of cytosolic and nuclear AR, ER and PR levels in the three separate lobes via hormonal manipulations of the adult animal including castration, steroid replacements, steroid antagonists, adrenalectomy, and pituitary grafts; 4) to determine the role of neonatal and prepubertal hormone exposure on imprinting the steroid sensitivity of the separate adult prostate lobes and to determine if these permanent alterations are mediated in part by the steroid receptors; 5) to determine if hormonal regulation and imprinting of steroid receptors alters the expression of the dorsal and lateral lobe-specific, androgen-regulated genes, M-40 and RWB using dot-hybridization to quantitate their mRNA levels. These studies are related to the normal and pathologic growth and development of the prostate gland. Understanding the differential regulation of steroid receptors and receptor-mediated growth and function of the three separate lobes may help explain why the ventral, dorsal and lateral lobes exhibit selective predilection for the development of prostatic adenocarciroma. Moreover, the lateral lobe is believed to be analogous to the outer region of the human prostate where cancerous lesions originate. Since the development of prostatic cancer and BPH are steroid-dependent, comparing and contrasting the control of steroid receptors among the lobes may provide valuable insights into the mechanisms of malignancy in this organ.
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