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Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation.
Am J Physiol Endocrinol Metab 2009; 296(6):E1335-43AJ

Abstract

Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell "shedding" into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a "gland within a gland." These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens.

Authors+Show Affiliations

Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19366880

Citation

Simanainen, Ulla, et al. "Androgen Sensitivity of Prostate Epithelium Is Enhanced By Postnatal Androgen Receptor Inactivation." American Journal of Physiology. Endocrinology and Metabolism, vol. 296, no. 6, 2009, pp. E1335-43.
Simanainen U, McNamara K, Gao YR, et al. Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation. Am J Physiol Endocrinol Metab. 2009;296(6):E1335-43.
Simanainen, U., McNamara, K., Gao, Y. R., & Handelsman, D. J. (2009). Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation. American Journal of Physiology. Endocrinology and Metabolism, 296(6), pp. E1335-43. doi:10.1152/ajpendo.00017.2009.
Simanainen U, et al. Androgen Sensitivity of Prostate Epithelium Is Enhanced By Postnatal Androgen Receptor Inactivation. Am J Physiol Endocrinol Metab. 2009;296(6):E1335-43. PubMed PMID: 19366880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation. AU - Simanainen,Ulla, AU - McNamara,Keely, AU - Gao,Yan Ru, AU - Handelsman,David J, Y1 - 2009/04/14/ PY - 2009/4/16/entrez PY - 2009/4/16/pubmed PY - 2009/7/17/medline SP - E1335 EP - 43 JF - American journal of physiology. Endocrinology and metabolism JO - Am. J. Physiol. Endocrinol. Metab. VL - 296 IS - 6 N2 - Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell "shedding" into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a "gland within a gland." These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens. SN - 0193-1849 UR - https://www.unboundmedicine.com/medline/citation/19366880/Androgen_sensitivity_of_prostate_epithelium_is_enhanced_by_postnatal_androgen_receptor_inactivation_ L2 - http://www.physiology.org/doi/full/10.1152/ajpendo.00017.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -