Stromal GR mediates long-term corticosteroid treatment induced epithelial hyperproliferation in mouse prostate — ASN Events
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  3. Stromal GR mediates long-term corticosteroid treatment induced epithelial hyperproliferation in mouse prostate

Stromal GR mediates long-term corticosteroid treatment induced epithelial hyperproliferation in mouse prostate (#307)

Ulla Simanainen 1 , Bin Zhao 1 , Jae Sung (Peter) Choi 1 , Maria Jaehne 1 , Yan Ru (Ellen) Gao 1 , Jan Tuckerman 2 , Hong Zhou 1 , David J Handelsman 1
  1. ANZAC Research Institute, Concord, NSW, Australia
  2. Institute of General of Zoology and Endocrinology , University of Ulm, Ulm, Germany

Glucocorticoids are used as a last resort treatment for prostate cancer but the cell-specific glucocorticoid receptor (GR) mediated actions and the role of endogenous glucocorticoids in prostate development are not understood. In this project, we first evaluated the influence of prostate epithelial GR mediated actions of physiological glucocorticoids in prostate structural development by comparing prostate epithelia selective GR knockout (peGRKO) and littermate wild-type (WT) mouse prostates at 8, 20 and 35 weeks of age. peGRKO males were generated using Cre/LoxP technique by crossing Probasin-Cre (1) and GR floxed (2) mice. In addition, as we previously hypothesized that long-term supraphysiological corticosterone treatment induced prostate hyperproliferation is mediated via prostate stromal GR (3) we verified the prostate cell-specific role of GR by treating sexually mature mice with corticosterone slow release pellets or placebo for 4 weeks. Prostate weights and histology in peGRKO males were comparable to WT at all timepoints analysed. Therefore, we conclude that prostate epithelial GR mediated glucocorticoid effects in mice have no major role in post-natal (post-natal inactivation) prostate development in mice. On the other hand, supraphysiological corticosterone treatment significantly (p<0.05) increased prostate weights and prostate epithelial cell proliferation (PCNA immunopositivity) in both WT and peGRKO males. The increased prostate weight was not due to the changes in circulating androgen levels supporting prostate specific GR mediated effects and demonstrating a significant role for prostate stromal GR mediated actions in prostate epithelial hyperproliferation induced by supraphysiological corticosterone treatment. In conclusion, sustained depot administration of corticosterone induced prostate hyperplasia is mediated via GR expressed predominantly in the stroma. Thus GR mediated actions in the prostate may have significant  differences in cell-specific effects that could be utilized for more rational approaches to the therapeutic use of glucocorticoids in prostate cancer treatment.

  1. Jin C, McKeehan K, Wang F. (2003) Prostate 57(2):160-4.
  2. Tronche, F., C. Kellendonk, et al. (1999). Nat Genet 23(1):99-103.
  3. Simanainen U, Lampinen A, et al. (2011) Prostate 71(3):289-97.
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