The American Journal of Pathology, Vol. 182, No.

6, June 2013

ajp.amjpathol.org

REVIEW
Androgen Receptor Roles in the Development of Benign
Prostate Hyperplasia
Kouji Izumi,*yzx{ Atsushi Mizokami,z Wen-Jye Lin,*yx{ Kuo-Pao Lai,*yx{ and Chawnshang Chang*yx{k

From the George H. Whipple Laboratory for Cancer Research* and the Departments of Pathology and Laboratory Medicine,y Urology,x and Radiation
Oncology (Wilmot Cancer Center),{ University of Rochester Medical Center, Rochester, New York; the Department of Integrative Cancer Therapy and
Urology,z Kanazawa University, Kanazawa, Japan; and the Sex Hormone Research Center,k China Medical University and Hospital, Taichung, Taiwan

Accepted for publication

February 4, 2013. Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased
volume of transitional zone and associated with increased stromal cells. It is known that androgen/
Address correspondence to
Chawnshang Chang, Ph.D., androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this
Box 626, Departments of signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of
Pathology and Urology, androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for
University of Rochester treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified,
Medical Center, 601 Elmwood and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in
Ave., Rochester, NY 14642. epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH devel-
E-mail: [email protected]. opment via epithelial cellestromal cell interaction with alterations of epithelialemesenchymal tran-
edu. sition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout
of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also
promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and
epithelial and stromal cells have been linked to BPH development, which has led to discovery of new
therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers
a potential therapeutic approach against BPH development. (Am J Pathol 2013, 182: 1942e1949;
http://dx.doi.org/10.1016/j.ajpath.2013.02.028)

Benign prostatic hyperplasia (BPH) is the most common reductase inhibitors (5-ARIs), which suppress testosterone
male benign proliferative disease, and approximately 8 conversion into dihydrotestosterone (DHT), have greater
million patients are estimated to visit physicians with the efficacy in reducing BPH volume, and clinical data indicate
diagnosis of primary or secondary BPH.1 The incidence of that the combination of 5-ARIs with a-blockers leads to the
gross enlargement of the prostate gland has been reported as best symptomatic response to date.8,9
40% in 70-year-old men, and microscopic foci of the prostate The above clinical data suggest that androgen/androgen
gland are present in up to 80% of these men.2 BPH patients receptor (AR) signaling plays key roles in development of
often have lower urinary tract symptoms, and need to be BPH and that targeting androgen/AR signaling could be
treated with surgery or medication. Although transurethral a major therapeutic approach for BPH. Nevertheless, the
resection of the prostate is the most common surgical treat-
ment for BPH worldwide, the procedure can lead to Supported by NIH grant CA156700, the George H. Whipple Professor-
complications (eg, bleeding, urethral stricture, incontinence) ship Endowment, the Taiwan Department of Health Clinical Trial, and
and may have limitations for people of advanced age.3e5 Research Center of Excellence grant DOH99-TD-B-111-004 (China
Although a-blockers are frequently prescribed for treatment Medical University, Taichung, Taiwan).
Disclosures: ASC-J9 was patented by the University of Rochester, the
of BPH and have a quick onset of action, within 3 to 5 days,6 University of North Carolina, and AndroScience Corporation, and then was
these drugs alone fail to shrink BPH volume and are licensed to AndroScience. Both the University of Rochester and C.C. own
often insufficient to eliminate symptoms.7 In contrast, 5-a equity in and receive royalties from AndroScience Corporation.

Copyright ª 2013 American Society for Investigative Pathology.

Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajpath.2013.02.028
 AR Roles in BPH Development

detailed mechanisms of androgen/AR signaling, and espe- symptoms.24,25 A double-blind, randomized trial for BPH
cially the pathogenic roles of AR in BPH,10 are still unclear. patients with the antiandrogen flutamide (750 mg/day for
In this review, we focus on the roles of AR in promoting 6 months) showed significantly decreased prostate volume by
prostate stromal cell growth11 and prostate epithelial cell 35%, compared with controls, within 6 months.26 However,
growth with increased epithelialemesenchymal transition these androgen-deprivation therapies with surgical or med-
(EMT).12 We also discuss how AR regulates development ical castration or with antiandrogens are no longer used as
of BPH through the inflammatory environment with mac- a standard treatment because of adverse reactions27,28 and
rophage infiltration, and address potential new therapeutic have been replaced by the 5-ARIs, which have better efficacy
approaches, such as targeting AR with the newly identified in suppressing development of BPH. A study of BPH patients
AR degradation enhancer ASC-J9 and/or targeting specific treated for 1 year with finasteride, a 5-ARI for 5-a reductase
inflammatory cytokines downstream of AR. type 2, showed a significant decrease in the size of the peri-
urethral area, as well as total prostate gland size, suggesting
Clinical Evidence of Androgen/AR Roles in that suppression of testosterone conversion into DHT could
lead to a significant decrease in the size of the prostate.29 The
Development of BPH
efficacy and safety profiles of finasteride in BPH patients
Basic Evidence for Androgen/AR Roles Supporting over a 12-month period also showed a 74% reduction in
Clinical Effects serum DHT levels, a 21% reduction in prostate volume,
and a significant improvement in urinary obstructive
The hormone dependency of development of BPH is well symptoms.30,31 However, finasteride treatment led to a 55%
documented, and androgen concentration or AR activity in decrease of DHT in epithelial cells of the TZ, with little effect
BPH patients has been a subject of study since 1895.13 One on stromal cells,32 even though 5-a reductase type 2 is
study in the 1980s found little difference in AR expression in expressed in both stromal and epithelial cells in the prostate.
prostate tissues isolated from either BPH patients or unaf- In contrast, another 5-ARI, dutasteride, inhibiting both type 2
fected control subjects.14 However, the serum concentration and type 1 of 5-a reductases (the latter expressed predomi-
of testosterone and DHT may change with age, with reduced nantly in epithelial cells33), showed a greater decrease in
serum testosterone in healthy old men, relative to that in DHT (98.4  1.2%) than did finasteride (70.8  18.3%).34
healthy younger men. In contrast, DHT levels are elevated, Taken together, these clinical studies suggest that androgen/
and serum DHT in BPH patients is significantly higher than AR may contribute to the increase of prostate volume, and
that in unaffected men at a similar age.15,16 Similar conclu- 5-ARIs with suppression of testosterone conversion into DHT
sions were also obtained recently in a large cross-sectional are effective medicines for reducing BPH size.
study that included 505 men aged 40 to 79 years (mean,
58 years); higher serum DHT levels and DHT/testosterone Limitations of Current 5-ARIs Targeting Testosterone
ratios were associated with larger prostate volume and higher Conversion into DHT for Treatment of BPH
prevalence of BPH.17
Tang et al18 found no difference in AR expression between Although 5-ARIs have been shown to reduce the volume of
the peripheral zone (PZ) and the transitional zone (TZ) in BPH, these may have some limitations. The Combination of
BPH. In other studies, although nucleic AR expression was Avodart and Tamsulosin (CombAT) study, with 4844 BPH
detected in both epithelial and stromal cells of hyperplastic patients, showed that combined therapy with both dutasteride
nodules, higher nuclear AR expression was detected in and the a-blocker tamsulosin was significantly superior to
prostate epithelial cells than in stromal cells.19,20 Others either monotherapy in reducing the relative risk of BPH
found higher 5-a reductase activity in stromal cells than in progression and symptoms.35 Later analysis, however, found
epithelial cells, with AR distributed evenly between epithe- that combined therapy was better than dutasteride mono-
lial and stromal cells.21,22 Importantly, the primitive BPH therapy in men with prostate volumes of 30 to <58 mL, but
nodules found in the periurethral area of the TZ had higher not in men with a prostate volume of <30 or 58 mL.36 The
concentrations of androgens and higher nuclear AR expres- benefit of combination therapy is thus greatest only in patients
sion than those in other prostate regions. These findings with larger BPH volumes, and a-blockers alone may be
suggest that androgen/AR signaling may play important roles sufficient to alleviate lower urinary tract symptoms in patients
in promoting the proliferation of epithelial and stromal cells with smaller BPH volumes; however, transurethral resection
in the periurethral area of the TZ, thus leading to develop- of the prostate may be needed for patients with the largest
ment of BPH with urinary obstruction (Figure 1).23 BPH volumes (approximately 60 mL).6 Importantly, 5-ARIs
have been reported to produce significant adverse sexual
Clinical Effects of Antiandrogens and 5-ARIs on BPH reactions, including decreased libido, erectile dysfunction, or
ejaculation problems.37e42 In addition, 5-ARIs may not be
Castrated BPH patients showed a marked decrease of pros- able to suppress completely the intraprostatic DHT in BPH
tatic volume after 2 to 3 months, and this volume reduc- patients, and the remaining DHT may still be able to trans-
tion correlated well with a relief of lower urinary tract activate AR and lead to development of BPH.

The American Journal of Pathology - ajp.amjpathol.org 1943

Izumi et al

Figure 1 Schematic of prostate structure. Most cases of prostate cancer occur in the peripheral zone (PZ), but BPH is caused by enlargement of the transitional
zone (TZ), especially in the periurethral area. The urethra penetrates the periurethral area, sandwiched between left and right adenoma and flattened in BPH.

AR Roles in Promoting Prostate Epithelial Cell epithelial cells may play positive roles in promoting devel-
Growth with Enhanced EMT in Development of BPH opment of BPH. In two studies from the 1990s, epithelial cell
content was significantly greater in the TZ than in the PZ,46
Epithelial AR Influences Cell Growth and epithelial cells were only 9.0% of BPH cells.47
However, epithelial cells may still play important roles in
Bello et al,43 using the human prostate epithelial cell line enhancing stromal cell growth via epithelial cellestromal cell
RWPE-1, found that addition of the synthetic androgen interaction. In coculture of primary human BPH stromal
mibolerone increased AR expression level and enhanced cell fibroblasts and epithelial cells, cell growth of cocultured cells
growth, and Silva et al44 found that DHT can promote human was significantly increased, compared to separate culture,48
primary prostate epithelial cell growth. These in vitro cell-line suggesting that epithelial cells may have a supportive role
data suggest that androgen/AR signaling may play positive in the growth of stromal cells in development of BPH. On the
roles in promoting prostate epithelial cell proliferation. other hand, stromal androgen/AR signaling may be able to
Wu et al45 generated conditional knockout AR mice that lack enhance the expression and/or release of growth factors that
AR only in prostate epithelial cells (pes-ARKO) and found that act on epithelial cells.49,50 Thus, prostate epithelial and
the pes-ARKO mice developed larger but less differentiated stromal cells may each support proliferation of the other cell
prostate with increased cell death, compared with wild-type type through growth factors in a paracrine manner.
littermates. Further analyses of each individual cell type
within the epithelium in pes-ARKO mice revealed that loss of
epithelial AR increased the proportion of CK5þ basal epithelial Epithelial Cells Contribute to Increased Stromal Cell
cells but decreased the proportion of CK8þ luminal epithelial Population via EMT and So Contribute to Development
cells, suggesting that luminal epithelial AR may play survival of BPH
roles and that basal epithelial AR may play suppressor roles in
maintaining homeostasis of prostate epithelial cells.45 It would EMT is a physiological process in which epithelial cells
be interesting to learn whether AR in epithelial cells of human acquire the motile characteristics of mesenchymal (stromal)
BPH has roles similar to those in the normal prostate. cells.51 EMT is characterized by decrease of epithelial
markers (eg, E-cadherin) and increase of mesenchymal
Epithelial Cells Contribute to Development of BPH via and transcriptional factors (eg, N-cadherin, vimentin, and
Epithelial CelleStromal Cell Interaction Snail).52 EMT is associated mainly with cancer progression,
including migration, invasion, and metastasis. Cancer cells
Clinical studies showing better efficacy of dutasteride than undergoing EMT may acquire invasive properties, entering
finasteride in suppressing BPH33,34 suggest that prostate the surrounding stromal cells and creating a favorable

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 AR Roles in BPH Development

microenvironment for cancer progression and metastasis.53 enhanced BPH-1 cell growth in a three-dimensional culture
Interestingly, Alonso-Magdalena et al12 found that EMT system, with increase of EMT in BPH-1 cells, and they
may also contribute to development of BPH. Although they demonstrated that increased TGF-b2 expression in BPH-1
found little evidence of proliferation in clinical human BPH cells and the addition of TGF-b2 neutralizing antibody
stromal cells, they found that 0.7% of basal cells and 0.4% suppressed THP-1 macrophages-mediated cell growth and
of luminal cells were positive for the proliferation markers EMT in BPH-1 cells. Importantly, they found that addition
Ki-67 and PCNA in the epithelium of some ducts.12 of AR in BPH-1 cells induced EMT gene expression in
Importantly, they found that regions of the ductal epithe- BPH-1 cells and promoted THP-1 macrophage migration
lium had lost their polarization and expressed little E-cad- during coculture with THP-1 cells. Addition of the AR
herin.12 Others reported that Snail2/Slug is the important degradation enhancer ASC-J9 also suppressed THP-1
transcriptional factor for TGF-b1einduced EMT of prostate macrophage-mediated cell growth in stably transfected AR
epithelial cells in BPH.54 These results suggest that EMT in BPH-1 cells.56 Similar data were also obtained when human
epithelial cells may also promote development of BPH BPH-1/THP-1 cells were replaced with mouse epithelial
(Figure 2). mPrE cells and mouse macrophage RAW264.7 cells in their
coculture system (Figure 3).56
AR Promotes Development of BPH by Influencing Taken together, these results demonstrate that epithelial
Infiltrating Immune Cell Migration toward Prostate AR may be able to enhance epithelial cell growth and EMT
Epithelial Cells induction by influencing recruitment of infiltrating immune
cells, which could then enhance development of BPH.
Inflammation with infiltrating macrophages influences
epithelial cells and may contribute to development of BPH. A AR Roles in Prostate Stromal Cell Growth That
study investigating the association between immune inflam- Promote Development of BPH
mation and AR expression in human BPH specimens from
prostatectomy showed that the total prostate volume was Stromal AR Contributes to Development of BPH
significantly higher in specimens with infiltrated inflam-
matory cells including B or T lymphocytes than in those It is well known that prostate cancer occurs predominantly in
without infiltrated inflammatory cells, suggesting that the the PZ, whereas BPH typically develops in the TZ.57 A study
immune inflammatory process may also contribute to de- in the 1990s reported that BPH is comprised of 88.4%
velopment of BPH.55 A recent study by Lu et al56 also showed stromal cells and 9.0% epithelial cells,47 and it is therefore
higher expression of the human macrophage marker CD68 in reasonable to think that stromal cells may play a major role in
human BPH specimens, further confirming that infiltrated development of BPH. Jiang et al57 found differences between
immune cells may be able to contribute to development of stromal cells in the TZ and those in the PZ with regard to AR
BPH. expression, DHT response, and cytokine expressions, and
Using coculture of human BPH-1 epithelial cells with they demonstrated that stromal cells in the PZ, but not the TZ,
human monocyte/macrophage THP-1 cells, Lu et al56 found are more supportive for prostate cancer epithelial cell growth;
that BPH-1 cells have the capacity to recruit more THP-1 however, little is known about whether stromal cells in the
cells. They found that recruited THP-1 cells subsequently TZ also contribute to development of BPH.57 In other studies,
DHT concentration and IGF-II activity were highest in the
periurethral area of the TZ in BPH,58 and basic fibroblast
growth factor (FGF) expression in stromal cells, but not in
epithelial cells, was reduced in BPH patients after finasteride
treatment.59 These results indicate that stromal cells in the TZ
may play an important role in development of BPH via
modulation of androgen/AR signaling and expression of
growth factors and cytokines.
Yu et al60 established the stromal smooth-muscle selec-
tive AR knockout (SM-ARKO) mouse model and found
decreased epithelial cell proliferation, with little change of
apoptosis and differentiation. They also found decreased
IGF-I expression in the prostates of SM-ARKO mice and
primary PS-1 stromal cells with AR knockdown, suggesting
that AR in stromal smooth-muscle cells may also contribute
to development of BPH via regulation of IGF-I signaling.
Figure 2 Schematic of EMT and proliferation in development of BPH. Yu et al61 also established the stromal fibroblast selective
Epithelial cells (both basal and luminal) undergo EMT, changing their shape AR knockout (FSP-ARKO) mouse model, and found that
over time to a more spindle-like form (arrows and circles), and proliferate. loss of AR in the stromal fibroblasts decreased proliferation

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Izumi et al

Figure 3 AR of epithelial cells attracts macrophages and interaction between epithelial cells, and macrophage infiltration increases secretion of TGF-b2
from epithelial cells. TGF-b2 promotes EMT of epithelial cells and finally forms spheres in three-dimensional culture. AR of stromal cells attracts macrophages
and interaction between stromal cells and infiltrated macrophages increases CCL3 secretion from both stromal cells and infiltrated macrophages. This
interaction induces the proliferation of stromal cells.

of epithelial cells with increased apoptosis, which may stimulating factor production in a paracrine manner to
involve the suppression of IGF-I and FGFs. facilitate stromal cell growth by elevating STAT3 activity
Lai et al62 established the double stromal AR knockout (Lai et al, unpublished data). The results indicated that
(dARKO) mouse model with selectively deleted AR in both stromal AR could modulate such epithelialestromal inter-
stromal fibroblasts and smooth-muscle cells, and found that acting signals, resulting in promotion of hyperplastic prostate
the size of the anterior prostate lobes was significantly growth (Lai et al, unpublished data). Furthermore, thera-
reduced, compared with those from wild-type littermate peutic approaches targeting stromal AR with ASC-J9
controls. Decreased proliferation and increased apoptosis of reduced prostate size and suppressed stromal cell prolifera-
the prostate epithelium in the dARKO mouse anterior tion (Lai et al, unpublished data).
prostate was also observed. Lai et al62 further confirmed Taken together, results from various stromal ARKO
these phenotypic changes with newly established immor- mouse models suggest that stromal AR may play crucial roles
talized prostate stromal cells (PrSC) from wild-type and in promoting stromal cell growth in both normal prostate and
dARKO mice. Mechanism dissection studies on the PrSCs in development of BPH.
from these mice again suggested that IGF-I may play key
roles in mediating positive roles of stromal AR in normal Stromal AR Promotes Development of BPH by
prostate growth. Influencing Infiltrating Macrophage Migration toward
The above in vivo mouse models showing stromal AR can Prostate Stromal Cells
promote normal prostate growth were recently further
extended to a prolactin transgenic (Pb-PRL tg) mouse BPH The potential influence of inflammatory infiltrating cells on
model. Mice with loss of AR in both stromal fibroblasts and stromal cell growth during development of BPH has also
smooth-muscle cells (dARKO/Pb-PRL tg) developed smaller been addressed.63,64 Wang et al65 found that the number of
prostates with a lower proliferative index and exhibited better infiltrated macrophages increased in stroma of human BPH
urination function and normal bladder volume, compared specimens, and that mouse stromal mPrSC cells had the
with wild-type/Pb-PRL tg mice (Lai et al, unpublished data). capacity to recruit more infiltrating macrophage RAW264.7
Mechanism dissection suggested that prolactin-induced cells in a coculture system. The consequent increase of
hyperplastic prostate growth involved the epithelial-stromal macrophage infiltration toward stromal cells could promote
interaction through epithelial autonomous prolactin/ the proliferation of stromal mPrSC cells.65
prolactin receptor action to regulate granulocyte colony- Mechanism dissection further revealed a remarkable
stimulating factor and granulocyte/macrophage colony increase of expression of the cytokine CCL3 in both mPrSC

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 AR Roles in BPH Development

stromal cells and RAW264.7 macrophages in a coculture of stromal cells, epithelial cells may still play an important
system, and addition of neutralizing CCL3 antibody resulted role in development of BPH via epithelial cellestromal cell
in a significant reduction of the migration of macrophage interaction or EMT. One such mechanism with positive roles
RAW264.7 cells toward stromal cells and a significant of AR involves increased recruitment of infiltrating macro-
reduction of macrophage-enhanced stromal mPrSC cell phages, with modulation of some cytokines. Targeting AR
proliferation during coculture.65 may therefore provide a reasonable therapeutic approach for
These in vitro coculture data were further confirmed using treatment of BPH. ASC-J9, which offers improved efficacy
an in vivo prolactin-induced BPH mouse model in a study in targeting AR and reduction in number or severity of
showing increased macrophage numbers and CCL3 expres- adverse effects, has the potential to become a next-generation
sion, compared with those from wild-type littermate con- therapy for BPH patients.
trols.65 Importantly, targeting stromal AR via deletion of the
stromal fibromuscular AR in the prolactin-induced BPH
model reduced the number of infiltrated macrophages and
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