In addition to androgens, Es have been suggested to play certain roles in the normal development and neoplastic growths of prostate gland, (1,2). However, the exact functional roles of Es and their receptors in the prostate are still unclear and remain controversial. The effects of Es on the prostate are complex and involve both direct and indirect actions.
The direct effects ofEs on the prostate or their roles in prostate cancer and benign prostatic hyperplasia are believed to be mediated through ERs, which are present in two subtypes, ERa and ERp. Both ER subtypes are expressed in human and rodent prostates, and exhibit distinct expression pattern in different tissue components. The expression ofboth ERa and ERp in prostate has developed into a view that the two ERs might play different functional roles in the prostate, and Es and their antagonists exert different actions on prostatic cells. However, studies from ER knock-out mouse models show that targeted disruption of either ER (a or p) or both ERs does not affect the prostatic phenotype and function (3), suggesting that other ER-related signaling pathways could exist and be involved in the prostatic growth and functions.
ERRs belong to the nuclear receptor subfamily III and consist of three closely related isoforms: a, p and y. All three ERR isoforms are highly homologous to ERs in their protein structures. However, they do not bind to Es or any other known physiological ligands, and thus they are classified as orphan nuclear receptors. Human ERRa and ERRP were first cloned in 1988 in kidney and heart cDNA libraries in a search for new members of ER (4). Similar to ERs, ERRs can bind to the consensus E responsive elements (ERE) and related E/retinoid receptor response element which is recognized by other orphan receptor (steroid factor-1), and thus they could regulate or modulate the transcription of genes, which are also regulated by ERs and other orphan nuclear receptors (5-7). In vitro studies show that ERRs are constitutively transactivated without binding to any known physiological ligands in positively expressed cells (8, 9), and they interact with a number of nuclear receptor coactivators (7,10-12), and also with ER by completing for same coactivators (13). A recent study suggests a mechanism of Ca2+-dependent transactivation of ERR as calmodulin can bind to ERRy (14). These studies suggest that ERRs could modulate or crosstalk with the classical E-signaling pathway mediated by ERs in regulating physiological activities in normal and cancer cells.
Based on this background, we are interested to investigate the expression pattern of ERRs in various human prostatic cell lines and prostatic tissues in order to reveal whether these receptors have any functional implication and roles in the prostate and prostate cancer.
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