An Indispensable Role of Androgen Receptor in Wnt Responsive Cells During Prostate Development, Maturation, and Regeneration

Abstract

Androgen signaling is essential for prostate development, morphogenesis, and regeneration. Emerging evidence indicates that Wnt/β-catenin signaling also contributes to prostate development specifically through regulation of cell fate determination. Prostatic Axin2-expressing cells are able to respond to Wnt signals and possess the progenitor properties to regenerate prostatic epithelium. Despite critical roles of both signaling pathways, the biological significance of androgen receptor (AR) in Axin2-expressing/Wnt-responsive cells remains largely unexplored. In this study, we investigated this important question using a series of newly generated mouse models. Deletion of Ar in embryonic Axin2-expressing cells impaired early prostate development in both ex vivo and tissue implantation experiments. When Ar expression was deleted in prostatic Axin2-expressing cells at pre-puberty stages, it results in smaller and underdeveloped prostates. A subpopulation of Axin2 expressing cells in prostate epithelium is resistant to castration and, following androgen supplementation, is capable to expand to prostatic luminal cells. Deletion of Ar in these Axin2-expressing cells reduces their regenerative ability. These lines of evidence demonstrate an indispensable role for the Ar in Wnt-responsive cells during the course of prostate development, morphogenesis, and regeneration, which also imply an underlying interaction between the androgen and Wnt signaling pathways in the mouse prostate. Stem Cells 2018;36:891-902.

Secreted Frizzled-Related Protein 4 (SFRP4) Is an Independent Prognostic Marker in Prostate Cancers Lacking TMPRSS2: ERG Fusions

“…Several studies report ERG activation as a Wnt signaling inducer [55,56] through frizzled-4 (FZD4) player, a direct antagonist of the Wnt inhibitory protein SFRP4 [57]. The striking correlation of SFRP4 and AR expression fits well with the established functional interaction of androgen receptor signaling and the Wnt pathway [58]. Whether a different prognostic outcome between the ERGpositive and negative subset of a biomarker is due to direct biological effects of ERG on the biomarker or indirect by blurring the expression scale due to ERG-induced higher expression of the biomarker is difficult to discern.…”

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

“…Ar Lox/Y mice were obtained from Dr. Guido Verhoeven [30]. To elicit genetic recombination, mice were intraperitoneally injected with 125 μg/g body weight of tamoxifen (TM; Sigma) suspended in corn oil (Sigma) [31,32]. To label Gli1-expressing cells in embryos, pregnant females were given a single intraperitoneal injection of TM (125 μg/g body weight).…”

“…For androgen supplementation, testosterone pellets (12.5 mg, Innovative Research of America) were placed subcutaneously in the backs of the mice. To prepare postnatal prostatic tissues for kidney capsule transplantation, mice were injected with TM on P14 [31,32]. On P21, the mice were euthanized and their prostates collected.…”

“…On P21, the mice were euthanized and their prostates collected. Individual prostatic lobes were separated and kept in DMEM (Gibco), 5% FBS (HyClone), and 1% Penicillin/Streptomycin (Gibco) while SCID mice were prepared for the kidney capsule transplantation procedure as described previously [31,32]. For tissue recombination assays, pregnant females were injected with TM (125 μg/g body weight) at E13.5 and euthanized on E15.5.…”

“…Five-micron serial sections were cut and processed from Clearify (American MasterTech Scientific) to PBS through a decreasing ethanol gradient. For histological assessment, hematoxylin and eosin staining was performed as described [31,32]. For IHC, slides were treated by boiling in 0.01 M citrate buffer (pH 6.0) for antigen retrieval, incubated in 0.3% H 2 O 2 for 15 min, blocked in 5% normal goat serum (Gibco) for 1 h, and incubated with appropriate antibodies (see S6 Table) diluted in 1% normal goat serum at 4˚C overnight.…”