The role of the androgen receptor in prostate development and benign prostatic hyperplasia: A review

doi:10.1016/j.ajur.2019.10.003

Asian Journal of Urology, 2020, 7 (3): 191-202 doi: 10.1016/j.ajur.2019.10.003

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The role of the androgen receptor in prostate development and benign prostatic hyperplasia: A review

Renee E. Vickman^a,Omar E. Franco^a,Daniel C. Moline^b,Donald J. Vander Griend^b,Praveen Thumbikat^c,Simon W. Hayward^a,*(

)

^a Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA
^b Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
^c Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

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Abstract

Benign prostatic hyperplasia (BPH) is a benign enlargement of the prostate in which incidence increases linearly with age, beginning at about 50 years old. BPH is a significant source of morbidity in aging men by causing lower urinary tract symptoms and acute urinary retention. Unfortunately, the etiology of BPH incidence and progression is not clear. This review highlights the role of the androgen receptor (AR) in prostate development and the evidence for its involvement in BPH. The AR is essential for normal prostate development, and individuals with defective AR signaling, such as after castration, do not experience prostate enlargement with age. Furthermore, decreasing dihydrotestosterone availability through therapeutic targeting with 5α-reductase inhibitors diminishes AR activity and results in reduced prostate size and symptoms in some BPH patients. While there is some evidence that AR expression is elevated in certain cellular compartments, how exactly AR is involved in BPH progression has yet to be elucidated. It is possible that AR signaling within stromal cells alters intercellular signaling and a “reawakening” of the embryonic mesenchyme, loss of epithelial AR leads to changes in paracrine signaling interactions, and/or chronic inflammation aids in stromal or epithelial proliferation evident in BPH. Unfortunately, a subset of patients fails to respond to current medical approaches, forcing surgical treatment even though age or associated co-morbidities make surgery less attractive. Fundamentally, new therapeutic approaches to treat BPH are not currently forthcoming, so a more complete molecular understanding of BPH etiology is necessary to identify new treatment options.

Key words： Prostate development Benign prostatic hyperplasia Androgen receptor Prostate stroma Inflammation

Received: 25 April 2019 Available online: 20 July 2020

Corresponding Authors: Simon W. Hayward E-mail: shayward@northshore.org

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Cite this article:

Renee E. Vickman,Omar E. Franco,Daniel C. Moline, et al. The role of the androgen receptor in prostate development and benign prostatic hyperplasia: A review[J]. Asian Journal of Urology, 2020, 7(3): 191-202.

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http://www.ajurology.com/EN/10.1016/j.ajur.2019.10.003 OR http://www.ajurology.com/EN/Y2020/V7/I3/191

Benign prostatic hyperplasia (BPH) in human prostate tissue. (A) Diagrams representing anatomical features of normal human prostate and BPH. BPH originates within the preprostatic region, containing the transition zone (TZ) and periurethral glands. A dashed line through the BPH diagram represents an approximate cross-sectional location of a whole-mount pathological view of BPH, as in (B) and (C). Human prostate cut along the transverse plan to observe a gross view (B) or whole mount H&E section (C). TZ and peripheral zone (PZ) are labeled and BPH nodules are indicated by black arrows. Modified from Aaron et al. [8].

Androgen receptor (AR) expression in prostatic cell types during development. Prostatic development is initiated with development of a urogenital sinus (UGS), followed by extension of prostatic buds forming an immature prostate gland. The adult prostate gland contains fully differentiated stromal and epithelial compartments which form a mature and functional organ. AR is initially expressed in just a proportion of the urogenital sinus mesenchyme (UGM). Epithelial cells gain AR expression throughout development. While only a subset of stromal cells (e.g. fibroblasts and smooth muscle cells) maintain AR expression in the adult prostate, virtually all luminal epithelial cells express AR.

General protein structures of androgen receptor (AR) and AR-V7. Full-length AR contains functional domains: NTD, N terminal domain; DBD, DNA-binding domain; H, hinge region; LBD, ligand-binding domain. General locations of the nuclear localization signal (NLS) and nuclear export signal (NES) are indicated, along with regions of transcriptional activation function (AF)-1 and AF-2 binding sites. AR-V7 contains the NTD and DBD, but alternative splicing of the gene truncates the protein leaving only cryptic exon 3 (CE3) at the C-terminus. Numbers flanking domains indicate the approximate amino acid at that location.

Summary of alterations in BPH. The normal adult prostate has low immune cell infiltration, basal AR expression, and basal levels of NF-κB activity, allowing for steady-state cell death/proliferation rates and maintenance of tissue homeostasis. In a prostate with BPH, there is increased collagen deposition and infiltration of inflammatory mediators, such as T cells and macrophages, resulting in a chronic inflammatory status within the prostate. Elevated inflammation results in NF-κB activation, which has been demonstrated to stimulate expression of SRD5A2, AR, and AR-V7. Inflammation, NF-κB activity, or AR could each be involved in the development of hyperplasia in epithelial or stromal cells observed in BPH nodules. AR, androgen receptor; BPH, benign prostatic hyperplasia; SRD5A2, 5α-reductase 2.

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