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Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract
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Expression of steroid hormone receptors and its
prognostic significance in urothelial carcinoma of
the upper urinary tract
Eiji Kashiwagi, Kazutoshi Fujita, Seiji Yamaguchi, Hiroaki Fushimi, Hiroki Ide,
Satoshi Inoue, Lungwani-Tyson TaichiMuungo, Mizushima, Leonardo O. Reis,
Rajni Sharma, George J. Netto, Norio Nonomura & Hiroshi Miyamoto
To cite this article: Eiji Kashiwagi, Kazutoshi Fujita, Seiji Yamaguchi, Hiroaki Fushimi, Hiroki
Ide, Satoshi Inoue, Taichi Mizushima, Leonardo O. Reis, Rajni Sharma, George J. Netto, Norio
Nonomura & Hiroshi Miyamoto (2016) Expression of steroid hormone receptors and its prognostic
significance in urothelial carcinoma of the upper urinary tract, Cancer Biology & Therapy, 17:11,
1188-1196, DOI: 10.1080/15384047.2016.1235667
To link to this article: https://doi.org/10.1080/15384047.2016.1235667
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Published online: 01 Nov 2016.
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3. adjacent or separate non-neoplastic urothelial tissue speci-
mens.9
However, there were only a few studies demonstrating
the expression of steroid hormone receptors, such as AR10-12
and ERb,11
in UUTUCs. In the current study, we aimed to
determine the expression status of these 5 steroid hormone
receptors in UUTUCs and corresponding non-neoplastic uro-
thelial tissues as well as to assess their correlations with clinico-
pathological features of the tumors.
Results
We immunohistochemically stained for AR, ERa, ERb, GR,
and PR in a set of TMA consisting of 99 UUTUC samples and
corresponding 80 normal-appearing urothelial tissues. Clinico-
pathological characteristics of the patient cohort were summa-
rized previously.13
Positive signals for all 5 receptors were
detected predominantly in nuclei of benign and malignant epi-
thelial cells (Fig. 1).
Table 1 summarizes the status of receptor expression in
non-neoplastic urothelium versus urothelial tumor tissues. AR,
ERa, ERb, GR, and PR were positive in 57%, 40%, 85%, 84%,
and 13% of benign urothelial tissues and 20%, 18%, 62%, 63%,
and 16% of UUTUCs, respectively. Thus, the positive rate of
AR (P < 0.001), ERa (P D 0.001), ERb (P D 0.001), or GR
(P D 0.002) was significantly lower in tumor than in non-neo-
plastic urothelium. There was no significant difference in PR
expression pattern between benign and carcinoma.
Next we analyzed the correlations of AR, ERa, ERb, GR, or
PR expression in UUTUCs with the clinicopathological profile
available for our patient cohort (Table 2). The positive rates
of AR and PR tended to be higher (P D 0.072) and lower
(P D 0.052) in male tumors (27% and 10%) than in female
tumors (10% and 26%), respectively, while no significant differ-
ence in the positivity of ERa (17% vs. 21%; P D 0.790), ERb
(58% vs. 69%; P D 0.296), or GR (67% vs. 56%; P D 0.395)
between genders was seen. The positive rates of AR (11% vs.
28%; P D 0.070) and ERb (51% vs. 72%; P D 0.056) were also
marginally reduced in renal pelvic tumors, compared with ure-
teral tumors, whereas differences in the positivity of ERa (22%
vs. 12%; P D 0 .272), GR (58% vs. 68%; P D 0.395), or PR (9%
vs. 20%; P D 0.155) between the 2 groups were not statistically
significant. In addition, there were no strong correlations of the
status of each receptor expression with the laterality of the
tumor, tumor grade, pT stage, or lymph node involvement.
We then performed Kaplan-Meier analysis coupled with the
log-rank test to assess possible associations between each recep-
tor staining and patient outcomes. There were no statistically
significant differences in tumor progression (Fig. 2) or cancer-
specific mortality (Fig. 3) between AR, ERa, ERb, GR, or PR
positivity and negativity. Nonetheless, patients with ERa-posi-
tive or PR-positive tumor had a significantly higher risk of can-
cer-specific mortality (P D 0.025), but not that of tumor
progression (P D 0.102), compared with those with ERa-nega-
tive and PR-negative tumor. In addition, in a total of 54
patients with pT3 or pT4 tumor, PR positivity correlated
with a significantly higher risk of cancer-specific mortality
(P D 0.040) (Fig. 4). Patients with pT3 or pT4 tumor negative
for both ERa and PR had also a significantly lower risk of can-
cer-specific mortality (P D 0.023). There were still no strong
associations between each of AR, ERa, ERb, or GR expression
and cancer-specific survival in this subgroup.
To determine whether ERa/PR status was an independent
prognosticator in patients with UUTUC, multivariate analysis
Figure 1. Immunohistochemistry of AR (A), ERa (B), ERb (C), GR (D), and PR (E) in
UUTUC specimens (original magnification: £400).
CANCER BIOLOGY & THERAPY 1189
5. was performed with the Cox model (Table 3). In the entire
cohort of the patients, positivity of either ERa or PR, or both
was found to correlate with cancer-specific survival [hazard
ratio (HR), 2.434; 95% confidence interval (CI), 1.055–5.617;
P D 0.037], but not with tumor progression (HR, 1.011; 95%
CI, 0.514–1.989; P D 0.197).
Discussion
In this study, we immunohistochemically determined the
expression levels of steroid hormone receptors, including AR,
ERa, ERb, GR, and PR, in a set of TMA consisting of 99 neph-
roureterectomy specimens. We obtained some results similar to
previous observations in UUTUC and/or bladder urothelial
tumor and others dissimilar to them.
Previous immunohistochemical studies have demonstrated
that the positive rates of AR expression range 16–55% in
UUTUC11,12
and 13–53% in BC.12,14-20
In accordance with our
current findings in UUTUCs, significant decreases in the AR-
positive rate have been reported in BCs, compared with non-
neoplastic urothelial tissues.14-16
In contrast, 2 other studies
showed no AR expression in normal bladder urothelium.18,20
In any of the studies involving UUTUCs,10-12
AR staining was
not performed simultaneously in normal/benign urothelial tis-
sues. Significant or marginal reduction of the AR positive rate
has also been found in high-grade and/or muscle-invasive
UUTUCs10,11
or BCs,12,14-16,18
compared with low-grade and/
or superficial tumors, while some of other studies19,21
as well as
our current study have shown no considerable correlations
between AR positivity and tumor grade or stage. Prognostic sig-
nificance of AR expression in BCs remains controversial: AR
expression correlates with better18,21
or worse14,20
outcomes,
whereas no strong correlations have been demonstrated in
other studies.16,17
Additionally, previous10
and current studies
assessed for AR expression in UUTUCs have failed to reveal its
values as a prognosticator.
No previous immunohistochemical studies have examined
ERa expression in UUTUC. Instead, ERa protein has been
immunohistochemically detected only in a subset (e.g. 1–5%)
of BC specimens,20,22-24
while our immunohistochemical analy-
ses have shown relatively high positive rates in BC (27%14
) and
UUTUC (18%, current results). Although the exact reasons for
the difference in the positive rate of ERa expression in BC
remain uncertain, PCR-based analyses have detected ERa tran-
scripts in virtually all the BCs examined.25
When compared
with BC14,23
as well as UUTUC (current study), these studies
showed elevated levels or positive rates of ERa protein expres-
sion in non-neoplastic urothelium. At least 2 of the studies
have also demonstrated down-regulation of ERa expression in
higher grade or stage BCs,14,23
while we failed to identify such a
tendency in UUTUC. Additionally, there have been no pub-
lished data suggesting the prognostic values of ERa expression
in urothelial tumors. Nonetheless, the current study revealed
that ERa negativity in combination with PR negativity was able
to predict better patient outcomes as an independent indicator.
Shyr et al.11
showed that 36 (43%) of 83 UUTUCs, including
44% of low-grade vs. 43% of high-grade tumors (P D 1.000) as
well as 47% of superficial vs. 51% of muscle-invasive tumors
(P D 0.815), were immunoreactive for ERb. In BCs, the positive
rates of ERb expression ranged from 22 to 76%,14,18,21,22,26,27
which was significantly lower than those in non-neoplastic
bladder tissues.14,27
A significant elevation in ERb positivity in
BC, compared with benign urothelium, was also documented.28
More recently, all the 410 BCs examined were found to be
Table 2. Correlations between steroid hormone receptor expression and clinicopathological profile of the patients.
AR positivity ERa positivity ERb positivity GR positivity PR positivity
Parameter n (%) P n (%) P n (%) P n (%) P n (%) P
Gender 0.072 0.790 0.296 0.395 0.052
Male (n D 60) 16 (27) 10 (17) 35 (58) 40 (67) 6 (10)
Female (n D 39) 4 (10) 8 (21) 27 (69) 22 (56) 10 (26)
Laterality 0.130 0.295 0.216 0.410 1.000
Right (n D 43) 12 (28) 7 (16) 30 (70) 29 (67) 7 (16)
Left (n D 56) 8 (14) 11 (20) 32 (57) 33 (59) 9 (16)
Tumor site 0.070a
0.272a
0.056a
0.395a
0.155a
Renal pelvis (n D 45) 5 (11) 10 (22) 23 (51) 26 (58) 4 (9)
Ureter (n D 50) 14 (28) 6 (12) 36 (72) 34 (68) 10 (20)
Both (n D 4) 1 (25) 2 (50) 3 (75) 2 (50) 2 (50)
Tumor grade 0.293 0.465 0.402 0.563 0.453
Low-grade (n D 15) 5 (33) 4 (27) 11 (73) 8 (53) 1 (7)
High-grade (n D 84) 15 (18) 14 (17) 51 (61) 54 (64) 15 (18)
Pathologic stage 0.301b
0.183b
0.831b
1.000b
0.779b
pTa (n D 19) 3 (16) 1 (5) 13 (68) 12 (63) 1 (5)
pT1 (n D 18) 2 (11) 3 (17) 11 (61) 11 (61) 4 (22)
pTa-pT1 (n D 37) 5 (14) 4 (11) 24 (65) 23 (62) 5 (14)
pT2 (n D 8) 3 (38) 2 (25) 4 (50) 5 (63) 2 (25)
pT3 (n D 48) 11 (23) 10 (21) 29 (60) 30 (63) 8 (17)
pT4 (n D 6) 1 (17) 2 (33) 5 (83) 4 (67) 1 (17)
pT2-pT4 (n D 62) 15 (24) 14 (23) 38 (61) 39 (63) 11 (18)
Lymph node involvement 0.450c
0.454c
1.000c
0.345c
0.684c
pN0 (n D 84) 19 (23) 17 (20) 52 (62) 55 (65) 15 (18)
pN1–3 (n D 12) 1 (8) 1(8) 8 (67) 6 (50) 1 (8)
pNx (n D 3) 0 (0) 0 (0) 2 (67) 1 (33) 0 (0)
a
Renal pelvis vs. Ureter.
b
pTa-pT1 vs. pT2-pT4.
c
pN0 vs. pN1–3.
CANCER BIOLOGY & THERAPY 1191
6. positive for ERb.24
Additionally, there have been considerable
increases,14,21,22,26
considerable decreases,27
or no significant
changes18,24
in the ERb positive rate in higher grade and/or
more invasive BCs. Furthermore, associations between ERb
overexpression and favorable21,24
or unfavorable14,18.28
progno-
sis of BC patients have been demonstrated. Our current data
show significant reduction of ERb positivity in UUTUC, com-
pared with non-neoplastic urothelium, as well as no strong cor-
relations between ERb expression and tumor grade/stage or
patient outcomes.
Our previous immunohistochemical analyses in the bladder
TMA showed that most of non-neoplastic urothelial tissues
(e.g., 96%) expressed the GR, which was significantly lower in
BCs (e.g. 87%).6,29
Similar tendency was seen in our UUTUC
specimens in the current study. To the best of our knowledge,
no other studies have assessed the expression of GR in UUTUC
or BC specimens. Meanwhile, loss of GR expression was
strongly associated with higher grade/stage BCs as well as
tumor recurrence/progression.29
However, these findings were
not observed in UUTUCs in the current study.
An immunohistochemical study revealed that PR was posi-
tive in non-neoplastic bladder urothelium from 18 of 20 male
children aged 1–12.30
However, subsequent studies showed no
PR signals in 19823
and 41024
BCs or PR expression in only
2%/4% of non-neoplastic urothelium/BC tissues, respectively.20
We here demonstrate that 13% of normal-appearing urothelial
tissues and 16% of UUTUCs, including 7% of low-grade vs.
18% of high-grade tumors (P D 0.453) as well as 14% of
Figure 2. Progression-free survival in 99 patients with UUTUC. Kaplan-Meier analysis was performed according to the positivity of AR, ERa, ERb, GR, or PR.
1192 E. KASHIWAGI ET AL.
7. superficial vs. 18% of muscle-invasive tumors (P D 0.779) are
immunoreactive for PR. More interestingly, PR positivity in
pT3 or pT4 UUTUCs, but not in entire 99 cases, was strongly
associated with disease-specific mortality. Indeed, in breast and
endometrial cancer cell lines, progesterone has been shown to
activate the mitogen-activated protein kinase signaling pathway
and thereby up-regulate human telomerase reverse transcrip-
tase31
whose activity is known to correlate with the progression
of urothelial tumors.32,33
Inconsistent with these observations,
in a study using a transgenic mouse model for BC, multiparous
females were shown to develop significantly smaller tumors
than nulliparous females, implying the preventing effects of
progesterone (and estrogens) on BC outgrowth.34
Further stud-
ies are required not only to correlate between PR expression
and the prognosis of UUTUC and/or BC in larger patient
cohorts but also to determine the role of progestogens-medi-
ated PR signals in urothelial tumor cell growth.
None of previous studies have demonstrated significant sex
differences in the expression pattern of AR, ERa, ERb, GR, or
PR in urothelial tumors.9
It is therefore assumed that the dis-
parities in the levels of circulating sex hormones and the sys-
temic hormonal milieu lead to differential activation of, for
instance, AR and ERs, in male vs. female urothelial cells. We
observed that the positive rates of AR and PR tended to be
higher in male and female UUTUCs, respectively. The signifi-
cance of these findings needs to be further investigated.
Remarkably, ureteral tumors were inclined to exhibit higher
positive rates of the expression of steroid hormone receptors,
such as AR and ERb, compared with renal pelvic tumors. A
similar trend was indeed seen in a previous study assessing AR
Figure 3. Cancer-specific survival in 99 patients with UUTUC. Kaplan-Meier analysis was performed according to the positivity of AR, ERa, ERb, GR, or PR.
CANCER BIOLOGY & THERAPY 1193
8. and ERb expression in UUTUCs.11
The underlying reasons for
these findings remain unclear but may include a difference in
tissue preservation between ureteral and renal pelvic tumors.
Delay to formalin fixation of surgical specimens is known to
lead to false-negative results in steroid hormone receptor
immunohistochemistry (e.g., ER/PR expression in breast can-
cer35
). It may have taken a longer time to complete tissue fixa-
tion of renal pelvic tumors, especially deep lesions, compared
with ureteral tumors, due to their anatomic locations/thickness
of the specimens around the tumors. Interestingly, when ana-
lyzed our current data in ureteral tumors only, there was a sig-
nificant decrease in AR positivity between low-grade [4 (67%)
of 6] versus high-grade [10 (23%) of 44] carcinomas
(P D 0.044), as seen in previous studies in ureteral tumor11
and
BC.14,18
However, there were no statistically significant differ-
ences in AR positivity between non-muscle-invasive vs. mus-
cle-invasive ureteral tumors as well as in the expression pattern
of ERa, ERb, GR, or PR between low-grade or non-muscle-
invasive versus high-grade or muscle-invasive ureteral tumors.
Emerging evidence has indicated that steroid hormone
receptor-mediated signals play a critical role in urothelial
tumorigenesis as well as tumor progression.5,9
In particular,
androgens, estrogens, and glucocorticoids have been shown to
modulate tumor outgrowth in a variety of cell line and animal
models. Accordingly, in these preclinical models, treatment
with clinically available drugs, including AR antagonists or
inhibitors being used in prostate cancer patients, ER modula-
tors being used in breast cancer patients (or estrogens), or
Figure 4. Cancer-specific survival in 54 patients with pT3 or pT4 UUTUC. Kaplan-Meier analysis was performed according to the positivity of AR, ERa, ERb, GR, or PR.
1194 E. KASHIWAGI ET AL.
9. glucocorticoids being used as anti-inflammatory, anti-immune,
or anti-tumor agents, resulted in inhibition of cell proliferation
and invasion in urothelial tumor lines as well as tumor develop-
ment and growth in animals. Recent retrospective clinical stud-
ies have also implied that androgen deprivation therapy for
prostate cancer prevents bladder cancer development and
recurrence.36,37
These findings further suggest potential appli-
cation of currently available therapeutic options used for other
pathological conditions to the treatment of urothelial tumors.
In conclusion, we observed that, consistent with prior obser-
vations in bladder specimens, the positive rates of AR, ERa,
ERb, and GR expression were significantly reduced in UUTUC,
compared with non-neoplastic urothelium included in the
same surgical specimens. PR was found to express in a subset
of non-neoplastic urothelial tissues and UUTUCs. However,
we failed to show significant differences in the expression of
these 5 steroid hormone receptors between low-grade/superfi-
cial vs. high-grade/muscle-invasive tumors. Meanwhile, PR
positivity alone was suggested to serve as a prognosticator in
patients with deeply invasive UUTUC. Furthermore, loss of
both ERa and PR in UUTUC, as an independent predictor,
was strongly correlated with better patient outcomes.
Materials and methods
UUTUC TMA was constructed with spotted triplicate tumor
samples and paired normal-appearing urothelial tissues from
99 patients who underwent radical nephroureterectomy per-
formed at Osaka General Medical Center, Osaka, Japan, as
described previously.13
Appropriate approval was obtained
from the institutional review board before construction and use
of the TMA.
Immunohistochemical staining was performed, using each
primary antibody [i.e. AR (clone N-20, dilution 1:200; Santa
Cruz Biotechnology), ERa (clone 6F11, dilution 1:100; Ven-
tana), ERb (clone H-150, dilution 1:200; Santa Cruz Biotech-
nology), GR (clone H-300, dilution 1:200; Santa Cruz
Biotechnology), PR (clone 16, dilution 1:100; Leica Biosys-
tems)], as described previously.14,29
All the stains were manu-
ally scored by a single pathologist (H.M.) who was blinded to
patient identity. The German Immunoreactive Score (range:
0–12) calculated by multiplying the percentage of immunoreac-
tive cells (0% D 0; 1–10% D 1; 11–50% D 2; 51–80% D 3; 81–
100% D 4) by staining intensity (0, negative; 1, weak; 2, moder-
ate; 3, strong) was considered negative (0; 0–1), weakly positive
(1C; 2–4), moderately positive (2C; 6–8), or strongly positive
(3C; 9–12).
The Fisher’s exact test was used to evaluate the association
between categorized variables. The survival rates were deter-
mined using the Kaplan-Meier method and comparison was
made by the log-rank test. In addition, the Cox proportional
hazards model was used to determine statistical significance of
prognostic indicators in a multivariate setting. Tumor progres-
sion was defined as the development of non-bladder lesions,
including recurrence at the nephroureterectomy site and lymph
node or visceral metastasis. Patients were followed up from ini-
tial diagnosis to the appearance of the event of interest or the
end of the study. P values less than 0.05 were considered statis-
tically significant.
Disclosure of potential conflicts of interest
The authors have no conflicts of interest to disclose.
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Table 3. Univariate and multivariate analysis of progression-free survival and cancer-specific survival in 99 patients with UUTUC.
Progression-free survival Cancer-specific survival
Univariate Multivariate Univariate Multivariate
Parameter HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P
Gender (male vs. female) 1.331 0.681–2.604 0.403 1.786 0.887–3.597 0.105 1.193 0.552–2.604 0.647 1.221 0.536–2.778 0.635
Laterality (left vs. right) 1.196 0.870–1.645 0.270 0.882 0.622–1.252 0.484 1.188 0.819–1.721 0.364 0.93 0.614–1.407 0.730
Tumor site (ureter vs. renal
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4.397 2.065–9.364 0.001 4.128 1.805–9.439 0.001 2.981 1.263–7.035 0.013 1.401 0.516–3.806 0.508
ERa/PR [ERa(C) or PR(C)
vs. ERa(-) and PR(-)]
1.729 0.881–3.393 0.111 1.011 0.514–1.989 0.197 2.341 1.082–5.062 0.031 2.434 1.055–5.617 0.037
HR D hazard ratio; CI D confidence interval.
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1196 E. KASHIWAGI ET AL.
![RESEARCH PAPER
Expression of steroid hormone receptors and its prognostic significance in urothelial
carcinoma of the upper urinary tract
Eiji Kashiwagia,b,
*, Kazutoshi Fujitac,
*, Seiji Yamaguchid
, Hiroaki Fushimie
, Hiroki Idea,b
, Satoshi Inouea,b,f,g
,
Taichi Mizushimaa,b,f,g
, Leonardo O. Reisa,b
, Rajni Sharmaa
, George J. Nettoa,b
, Norio Nonomurac
,
and Hiroshi Miyamotoa,b,f,g,h
a
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; b
Department of Urology, Johns Hopkins University
School of Medicine, Baltimore, MD, USA; c
Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan; d
Department of Urology,
Osaka General Medical Center, Osaka, Japan; e
Department of Pathology, Osaka General Medical Center, Osaka, Japan; f
Department of Pathology &
Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; g
Wilmot Cancer Institute, University of Rochester Medical Center,
Rochester, NY, USA; h
Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
ARTICLE HISTORY
Received 20 June 2016
Revised 8 August 2016
Accepted 4 September 2016
ABSTRACT
To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma
(UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-a (ERa), ERb,
glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired non-
neoplastic urothelial tissues. AR/ERa/ERb/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which
was significantly lower (except PR) than in benign urothelial tissues [57% (P < 0.001)/40% (P D 0.001)/85%
(P D 0.001)/84% (P D 0.002)/13% (P D 0.489)]. There were no significant associations between each
receptor expression pattern and histopathological characteristic of the tumors including tumor grade/
stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor
expression in these 99 patients. However, patients with UUTUC positive for either ERa or PR had a
significantly higher risk of disease-specific mortality (P D 0.025), compared with those with UUTUC
negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of
disease-specific mortality (P D 0.040). Multivariate analysis further identified the expression of ERa and/or
PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio,
2.434; P D 0.037). Thus, in accordance with previous observations in bladder specimens, significant
decreases in the expression of AR/ERa/ERb/GR in UUTUC, compared with that in non-neoplastic
urothelium, were observed. Meanwhile, the negativity of both ERa and PR in UUTUC as well as the
negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator.
Abbreviations: AR, androgen receptor; BC, bladder cancer; ER, estrogen receptor; GR, glucocorticoid receptor; PR,
progesterone receptor; TMA, tissue microarray; UUTUC, upper urinary tract urothelial carcinoma
KEYWORDS
Androgen receptor; estrogen
receptor; glucocorticoid
receptor;
immunohistochemistry;
progesterone receptor;
prognosis; upper urinary
tract urothelial carcinoma
Introduction
Upper urinary tract urothelial carcinoma (UUTUC) is a rela-
tively rare but often aggressive urologic malignancy.1
Due to its
lower incidence compared with that of bladder cancer (BC),
the pathogenesis of UUTUC remains far from fully understood,
while there are some similarities between molecular/genetic
features of UUTUC and BC.2,3
In addition, there are currently
no reliable prognostic biomarkers of UUTUC in clinical use.
Men have a substantially higher risk of BC than women.4
Gen-
der-specific differences in the incidence and progression of
UUTUC have also been reported.1
Meanwhile, a growing body of
preclinical evidence has indicated the involvement of sex hor-
mones and their receptor signals in urothelial cancer outgrowth,5
which may clearly explain some of the gender disparity. Specifi-
cally, androgen receptor (AR) activation correlates with induction
of urothelial tumorigenesis and tumor progression. On the other
hand, both stimulatory and inhibitory effects of estrogens/
estrogen receptors (ERs) on these, which appear to be cell-specific
and dependent on the functional activity of ERa and ERb, have
been documented. In contrast, little is known about the functions
of another class of sex hormones, progestogens, including proges-
terone that generally counteracts estrogen action, and progester-
one receptor (PR) signals in urothelial cancer.
In addition to these sex hormone receptors, a steroid hormone
receptor, glucocorticoid receptor (GR), has been studied in BC
and found to function as a tumor suppressor.6-8
We have demon-
strated that glucocorticoids directly mediate GR activity in BC
cells and strongly inhibit BC cell invasion and metastasis. It is
noteworthy, however, that some natural or synthetic glucocorti-
coids, such as hydrocortisone and dexamethasone, contradicto-
rily promote BC cell proliferation via inhibiting apoptosis
particularly that induced by a chemotherapeutic drug cisplatin.6,7
Previous immunohistochemical studies have shown the lev-
els of AR, ERa, ERb, GR, and PR expression in BC and
CONTACT Hiroshi Miyamoto hiroshi_miyamoto@urmc.rochester.edu
*These authors have contributed equally to this work.
© 2016 Taylor & Francis Group, LLC
CANCER BIOLOGY & THERAPY
2016, VOL. 17, NO. 11, 1188–1196
http://dx.doi.org/10.1080/15384047.2016.1235667](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)