This version published online on October 26, 2006
Endocrinology, doi:10.1210/en.2006-0906
Submitted on July 7, 2006
Accepted on October 16, 2006
Essential role for estrogen receptor {beta} in stromal-epithelial regulation of prostatic hyperplasia
STEPHEN J. MCPHERSON, STUART J. ELLEM, EVAN R. SIMPSON, VLADIMIR PATCHEV, KARL-HEINRICH FRITZEMEIER, and GAIL P. RISBRIDGER*
Centre for Urological Research, Monash Institute of Medical Research, Monash University Clayton, Australia, 3168 (SJM, SJE, GPR); Prince Henry's Institute, Melbourne, Australia, 3168 (ERS)Schering AG, CRBA Gynecology and Andrology, Berlin, Germany, 13342 (VP, K-HF)
* To whom correspondence should be addressed. E-mail: gail.risbridger@med.monash.edu.au.
Estrogens, acting via estrogen receptors {alpha} and {beta} (ER{alpha} and ER{beta}), exert direct and indirect actions on prostate growth and differentiation. Previous studies using animal models to determine the role of ER{beta} in the prostate have been problematic because centrally mediated response to estrogen results in reduced androgen levels and prostatic epithelial regression, potentially masking any direct effects via ER{beta}. This study overcomes this problem by using the estrogen-deficient aromatase knockout (ArKO) mouse and tissue recombination to provide new insight into estrogen action on prostate growth and pathology.
Homo- and heterotypic ArKO tissue recombinants revealed stromal aromatase deficiency induced hyperplasia in normal prostatic epithelium due to disruption of paracrine interaction between stroma and epithelia. Treatment of tissue recombinants with an ER{beta} specific agonist demonstrated that stimulation of ER{beta} elicits anti-proliferative responses in epithelium that are not influenced by alterations to systemic androgen levels or the activation of ER{alpha}. Additionally, work performed with intact ArKO mice demonstrated that the administration of an ER{beta} specific agonist ablated pre-existing prostatic epithelial hyperplasia, while an ER{alpha} specific agonist did not. Therefore, failed activation of ER{beta}, resulting from local stromal aromatase deficiency, in conjunction with increased androgen levels, results in increased epithelial cell proliferation and prostatic hyperplasia. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguishes them from those that adversely alter prostate growth and differentiation. This highlights the potential of SERMS, rather than aromatase inhibitors, for the management of dysregulated prostate growth. |
