Document Detail


Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation.
MedLine Citation:
PMID:  19366880     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ulla Simanainen; Keely McNamara; Yan Ru Gao; David J Handelsman
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-04-14
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  296     ISSN:  0193-1849     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-26     Completed Date:  2009-07-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E1335-43     Citation Subset:  IM    
Affiliation:
Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia.
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MeSH Terms
Descriptor/Qualifier:
Androgens / metabolism*,  pharmacology
Animals
Apoptosis / physiology
Body Weight
Cell Differentiation / physiology
Cell Proliferation
Dihydrotestosterone / metabolism,  pharmacology
Epithelial Cells / cytology,  physiology*
Genotype
Integrases / genetics
Male
Mice
Mice, Knockout
Orchiectomy
Organ Size
Precancerous Conditions / metabolism,  pathology,  physiopathology
Prostate / pathology,  physiology*
Prostatic Hyperplasia / metabolism,  pathology,  physiopathology*
RNA, Messenger / metabolism
Receptors, Androgen / genetics*,  metabolism
Regeneration / physiology
Stromal Cells / cytology,  physiology
Testosterone / metabolism,  pharmacology
Chemical
Reg. No./Substance:
0/Androgens; 0/RNA, Messenger; 0/Receptors, Androgen; 521-18-6/Dihydrotestosterone; 58-22-0/Testosterone; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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