Inability of Cytoplasmic or Nuclear Androgen Receptor Content
or Distribution to Distinguish Benign from Carcinomatous
Human Prostate
Sydney A. Shain, Lester S. Gorelic, Robert W. Klipper, et al.
Cancer Res 1983;43:3691-3695. Published online August 1, 1983.
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Copyright © 1983 American Association for Cancer Research
[CANCER RESEARCH 43. 3691-3695,
August 1983]
Inability of Cytoplasmic or Nuclear Androgen Receptor Content or
Distribution to Distinguish Benign from Carcinomatous Human
Prostate1
Sydney A. Shain,2 Lester S. Gorelic, Robert W. Klipper, Ibrahim Ramzy, Donald E. Novicki, Howard M. Radwin,
and Donald L. Lamm
Department of Cellular and Molecular Biology, Southwest Foundation for Research and Education [S. A. S., L S. G., R. W. K.}; Division of Urology, Audie L Murphy
Memorial Veterans Hospital [S. A. S., D. L. L.¡;Departments of Surgery [H. M. R., D. L. L] and Pathology [I. R.], University of Texas Health Science Center; and
Department of Urology, Wilford Hall United States Air Force Medical Center [D. E. N.], San Antonio, Texas 78284
ABSTRACT
We used exchange saturation analysis at 15°to quantitate
total cytoplasmic and nuclear androgen receptor content of 70
patient specimens. Cytoplasmic androgen receptor contents
(fmol/mg DMA) for eight specimens of clinically benign hyperplasia, 14 specimens of historically
hyperplastic prostate obtained
at cystoprostatectomy,
and carcinomatous and noncarcinomatous prostate obtained at radical prostatectomy for prostatic
carcinoma, 48 specimens, respectively, were 830 ±165 (mean
±S.E.), 890 ±445,955 ±240, and 750 ±95. Nuclear androgen
receptor contents of these same specimens, respectively, were
275 ±40, 235 ±30, 345 ±25, and 350 ±30; whereas, the
values of the cytoplasmic/nuclear receptor content, respectively,
were 3.25 ±0.55, 3.05 ±0.80, 2.50 ±0.50, and 2.80 ±0.40.
Multiway analyses of variance of these cross-sectional data
showed that there was no significant difference (p > 0.05)
between group mean values. This result principally reflects the
fact that the families of values for the four tissue groups were
highly heterogenous with broad overlap. The results would not
appear to be unduly influenced by carcinomatous epithelial cell
content of the specimens, because cytoplasmic and nuclear
androgen receptor content were not related to specimen carci
nomatous epithelial cell content. Paired analyses of receptor
content in carcinomatous and noncarcinomatous prostate spec
imens from the same prostate showed enhanced or unchanged
receptor content in 58% (cytoplasmic) and 62% (nuclear) of
specimens. Our studies show that cross-sectional analyses of
androgen receptor content fail to distinguish carcinomatous pros
tate from noncarcinomatous prostate. However, paired analyses
of these tissues from the same gland identify distinguishing
differences. The clinical relevance of these observations remains
to be examined.
INTRODUCTION
Quantitation of estrogen receptor content of human breast
carcinoma biopsies is an established diagnostic aid for treatment
selection and assessing prognosis (3, 11, 13, 23). A portion of
the success of this diagnostic may be attributed to the profound
physiological differences which characterize nonlactating and
1Supported
in part by USPHS Grant CA 23668 from the National Cancer
Institute, Department of Health and Human Services. The views herein expressed
are those of the authors and do not necessarily reflect the views of the United
States Air Force.
2 To whom requests for reprints should be addressed, at Southwest Foundation
for Research and Education, West Loop 410 and Military Drive, San Antonio,
Texas 78284.
Received April 19,1983; accepted May 9,1983.
carcinomatous breast tissue. The former contains a scant epi
thelial cell population which, in human (2,7), mouse (16,22), and
rat (5), is essentially devoid of estrogen receptors. By contrast,
many breast carcinomas contain significant quantities of estro
gen receptors (3, 11, 13, 23). Consequently, the diagnostic
evaluates a positive signal in breast carcinoma, receptor present,
against a negative signal in normal nonlactating breast, receptor
absent.
Many investigators have established that noncarcinomatous
(1, 4, 6, 8, 15, 17, 19-22) and carcinomatous (1, 6, 8, 15, 17,
21) human prostatic tissues contain androgen receptors. Inci
dental comparisons of nuclear (1, 6, 8,15, 21 ) or cytoplasmic (1,
6, 17, 21) androgen receptor content in carcinomatous and
noncarcinomatous human prostate specimens have been de
scribed. Detailed comparative analysis of cytoplasmic and nu
clear androgen receptor content and distribution in well-charac
terized carcinomatous and noncarcinomatous human prostate
specimens has not been described. As part of studies to develop
a detailed profile of the properties of carcinomatous and noncar
cinomatous human prostate, we have performed such an anal
ysis. This report details the results of our systematic evaluation.
MATERIALS AND METHODS
Patient Specimens. All tissues were collected at the time of diagnostic
or palliative surgery after obtaining informed consent. Tissue was dis
sected by a pathologist immediately following excision and was grossly
separated into noncarcinomatous (benign) and carcinomatous prostate.
Tissues were processed and transported to the research laboratory as
described previously (21). Representative samples of all specimens were
obtained prior to freezing and were processed (21) for histological
analysis. The studies described in this report were performed with tissues
obtained from 47 patients: benign hyperplastic prostate obtained at
prostatic enucleation, 8 patients; histologically hyperplastic prostate ob
tained at cystoprostatectomy
for bladder carcinoma, 14 patients; and
carcinomatous and noncarcinomatous prostate obtained at radical pros
tatectomy for prostatic carcinoma, 25 patients.
Histological Evaluation. All tissues were step-serial sectioned, and
slides were prepared and evaluated at 3 levels, the top, middle, and
bottom of the block. Diagnoses were made by reading at least one slide
at each level for each specimen. Epithelial cell content and carcinomatous
cell content of all specimens were visually estimated. Evaluations were
performed simultaneously by a surgical pathologist (I. Ramzy) and an
experienced, trained nonpathologist (S. A. Shain).
Chemicals. 17a-[mef/>y/-3H3]R1881 (specific activity, 87 Ci/mmol) and
radioinert R1881 were obtained from New England Nuclear (Boston,
Mass.). Sodium molybdate, dithiothreitol, phenylmethylsulfonyl fluoride,
and human -y-globulin (Fraction II) were from Sigma Chemical Co. (St.
Louis, Mo.). Norit was from Fisher Scientific Co. (Fairtown, N. J.), and
dextran T-70 was from Pharmacia Fine Chemicals, Inc., (Piscataway,
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Copyright © 1983 American Association for Cancer Research
S. A. Shain et al.
N. J.). All other chemicals were reagent grade and were used as obtained
from the manufacturer. Solutions were prepared in water that had been
distilled, detonized, and redistilled from glass.
Tissue Fractionation and Androgen Receptor Quantitation. Cytoplasmic and nuclear tissue extracts were prepared at 2-4° precisely as
3490
A MEDIAN
•MEAN
2500
described previously (21). Cytoplasmic and nuclear androgen receptor
content were determined by exchange saturation analysis during incu
bation at 15°(21). The exact incubation protocols and ligand concentra
o
0<
tions used were as described previously (21). Saturation data were
analyzed both by Scatchard (18) representation, in order to monitor for
possible contribution of secondary binding components to measured
receptor content, and by double-reciprocal plot analysis (20), for deter
2000
mination of receptor site content by simple linear regression analysis
(14).
Other Methods. Protein was determined by the method of Lowry ef
a/. (9) using bovine serum albumin as standard. Interference due to
dithiothreitol was eliminated by a modification of the iodogen procedure
of McClard (10), which we have described previously (21). Salmon testis
DMA was used as standard for quantitation of DNA as described previ
ously (21).
Statistical Analysis of Data. Because replicate saturation analyses
indicated that no definable relationship characterized the interaction of
the dependent variable (fmol bound)"1 and the independent variable
(IR18811) '. we used unweighted
4730
6643
2
a*
1500
I
e
•o
1000
«
Hl
°
t
linear regression analyses of double-
500
reciprocal plots to determine receptor site content and R1881 binding
affinity. We used analysis of co vari ance to determine the significance of
the slope of regressed lines (27). Differences among group means were
evaluated by one-way analysis of variance, and a posteriori contrasts
were evaluated by the Student-Newman-Keuls
procedure (12).
BPH
Cystoprosto-
Radical
tectomy
RESULTS
Prostatectomy
Benign
Androgen Receptor Content and Distribution in Cross-Sec
tional Specimens of Human Prostatic Tissues. Cytoplasmic
androgen receptor content of human prostatic tissues varied
from zero (one case) to 6640 fmol per mg DNA (Chart 1). The
families of values for cytoplasmic receptor site content were
similar with broad overlap. As anticipated from inspection of the
data, mean receptor site content of each of the 4 families (Chart
1) was not significantly different (p > 0.05). Interestingly, cyto
plasmic receptor content of a significant number of benign histologically hyperplastic specimens, obtained at radical prostat
ectomy, clustered at values of less than 500 fmol per mg DNA.
The same result characterized cytoplasmic androgen receptor
site content of histologically hyperplastic prostate obtained at
cystoprostatectomy for bladder carcinoma (Chart 1). By contrast,
most specimens of clinically benign hyperplastic prostate con
tained greater than 500 fmol cytoplasmic androgen receptor per
mg DNA. The mean and median values for these analyses are
summarized in Table 1.
Nuclear androgen receptor content of human prostatic tissues
ranged between 65 and 700 fmol per mg DNA (Chart 2). As was
the case for cytoplasmic androgen receptor content, the families
of values for nuclear androgen receptor content were similar
with broad overlap. Mean nuclear androgen receptor site content
(Chart 2) for each of the 4 families was not significantly different
(p > 0.05). There was a tendency for nuclear receptor site
content to be higher in radical prostatectomy specimens when
compared to enucleation (benign prostatic hyrjerplasia) or cys
toprostatectomy specimens (Chart 2). Mean and median values
for these analyses are summarized in Table 1.
The value of the ratio of cytoplasmic androgen receptor con
tent/nuclear androgen receptor content ranged from 0.35 to
Carcinoma
Chart 1. Cytoplasmic androgen receptor content of human prostatic tissues.
BPH, benign prostatic hyperplasia.
Table 1
Cytoplasmic and nuclear androgen receptor content and distribution in human
prostatic tissues
Tissues were obtained and analyzed for receptor content as described in the
text.
Receptor content (fmol/mg DNA)
Procedure/tissue
type
Enucleation
Clinical BPH
Cystoprostatectomy
Histológica! BPH
Radical prostatectomy
Benign"
Carcinoma
*C/N, cytoplasmic
Cytoplasmic
Receptor
distribution
(C/N)a
Nuclear
830 ±165°(755)° 275 ±40 (240)
3.25 ±0.55
890 ±445 (440)
3.05 + 0.80
235 + 30(230)
955+ 240 (615) 345±25(310) 2.50±0.05
750+ 95 (650) 350±30(345) 2.80±0.40
receptor content/nuclear
receptor content;
BPH, benign
prostatic hyperplasia, principally mixed glandular and straniai.
0 Mean ±S.E.
'' Numbers in parentheses, median value.
" Benign tissues were free of carcinoma and principally consisted of histotogical
hyperplasia as described for benign prostatic hyperplasia.
greater than 10.0 (Chart 3). The value of this ratio was equal to
or greater than one for 85% (58 of 68) of the tissues analyzed
(Chart 3). Mean values of the receptor ratio for the 4 families of
specimens were not significantly different. Within a family, there
was a broad distribution of values for the receptor ratio, and
there was also marked overlap of values between families (Chart
3). Mean and median values for these analyses are reported in
Table 1.
Paired Analyses of Cytoplasmic and Nuclear Androgen
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Androgen Receptors of Benign and Carcinomatous Prostate
. .A
1
o
o
MEDIAN•
MEAN."••••
600
o
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o
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matched carcinomatous specimen. Analysis of nuclear androgen
receptor content in paired specimens revealed 5 of 13 with
diminished, 6 of 13 with enhanced, and 2 of 13 with unchanged
receptor content when benign tissue was compared to the paired
carcinomatous specimen (Chart 5).
Effect of Relative CarcinomatousEpithelial Cell Content on
Specimen Cytoplasmicand Nuclear Androgen Receptor Con
tent. Becausecarcinomatousepithelialcell contentof the tissue
»3»
-A-.JÉ?5•-...5,
*i
200
2000-
i "
*A•I*.
o
O
BPH
Cystoprosta-
Radical
tectomy
Prostatectomy
Benign
Carcinoma
Chart 2. Nuclear androgen receptor content of human prostatic tissues. BPH,
benign prostatic hyperplasia.
iA
10.08.06.04.02.0
MEDIAN
MEAN••
o
.5!
o
-. • -••*•
.
u
o
"E
</>
.•**•-•
"o.
o
Benign
o
o
Corcinomo
Chart 4. Cytoplasmic androgen receptor content of paired specimens of carci
nomatous and benign (noncarcinomatous) tissues of prostate glands from 12
patients.
~0
(T
*-.;•
•
CL
0>
*-
-A-BPH
O
0>
cr
•%
750
§
o
0---**-A-••
si
CystoprostaRadicaitectomy
500
ü O
ProstatectomyBenign
Carcinoma
Charts. Value of the ratio of cytoplasmic receptor content/nuclear
content in human prostatic tissues. BPH, benign prostatic hyperplasia.
receptor
^ o
e I
<
3-
350
1
Receptor Content of Carcinomatous and Benign Prostatic
Tissue Obtained at Radical Prostatectomy. Pairedanalysesof
cytoplasmic androgen receptor content in benign (noncarcinom
atous, histological hyperplasia) and carcinomatous prostate
specimens from the same gland (Chart 4) revealed 5 of 12 with
diminished, 5 of 12 with enhanced, and 2 of 12 with unchanged
receptor content when benign tissue was compared to the
AUGUST
Benign
Carcinoma
ChartS. Nuclear androgen receptor content of paired specimens of carci
nomatous and benign (noncarcinomatous) tissues of prostate glands from 13
patients.
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1983
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Copyright © 1983 American Association for Cancer Research
S. A. Shain et al.
Nucleor
y=-0.627X+393
r =0.159
500
z
o
H
h
+
Cytoplasmic
y =-l.884X + 878
r =0.134
'
2000
«
O 1500
o
er
IODO
e
500
20
40
60
80
100
Carcinomotous Epithelium Content
(% total epithelium)
Chart 6. Relationship between prostate specimen carcinomatous epithelial cell
content and cytoplasmic or nuclear androgen receptor content.
specimen conceivably could influence receptor content, we per
formed a preliminary evaluation of this relationship. Both cyto
plasmic and nuclear androgen receptor contents of carcinoma
containing prostate specimens were independent of relative carcinomatous epithelial cell content (Chart 6). The slopes of these
regression lines (Chart 6) were not significantly different (p >
0.05) from zero. In all cases, epithelial cell content was estimated
to be at least 40% of total specimen cell content. In the majority
of cases, epithelial cell content was 50 to 75%.
DISCUSSION
We have shown that mean cytoplasmic androgen receptor
contents (fmol per mg DNA) of benign clinical hyperplastic pros
tate, benign histological hyperplastic prostate (cystoprostatectomy), noncarcinomatous (histologically hyperplastic) prostate
from carcinoma-containing glands, and carcinomatous primary
prostatic tissues are statistically indistinguishable. This result
principally reflects the wide variation in individual values obtained
for specimens from the 4 families of tissue (Chart 1). Moreover,
the mean values for the family of cystoprostatectomy specimens
and benign radical prostatectomy
specimens are heavily
weighted by the outlier values; compare the value of the mean
and median for these groups (Chart 1; Table 1). When the outlier
values are deleted, the mean values for these 2 families of
samples, respectively, are 450 ±70 and 656 ±130.
This analysis supports the impression that cytoplasmic andro
gen receptor content of histological hyperplastic prostate tends
to be less than that of clinical hyperplastic or carcinomatous
prostatic specimens. While this interpretation may have rele
vance for the physiology of prostatic dysfunction, it has little
relevance as a diagnostic, because androgen receptor content
of benign tissue in carcinomatous glands is represented by a
family of values including those characteristic of both cystopros
tatectomy and carcinomatous tissues (Chart 1). As expected
from inspection of the data in Chart 1, deletion of the outlier
values for the family of benign radical prostatectomy tissues
leaves a family of specimens indistinguishable, with regard to
mean value and distribution of family members, from that for
carcinomatous tissues. With regard to family mean cytoplasmic
androgen receptor values, our results are comparable to pre
vious observations (4, 23); however the current studies suggest
that analysis of means has limited significance, since all speci
mens appear to define a single population consisting of families
representing groups within the larger population.
The range of values for nuclear androgen receptor content of
these specimens was considerably less than that for cytoplasmic
androgen receptor content (compare Charts 1 and 2). Although
mean and median values for nuclear receptor content of each of
the 4 families of specimens were not significantly different,
receptor content of specimens from radical prostatectomy tis
sues tended to be greater than that of the other 2 families of
specimens (Chart 2). The absence of a significant reduction in
either nuclear (Chart 2) or cytoplasmic (Chart 1) androgen recep
tor content of carcinomatous specimens, when expressed as
receptor sites per mg DNA, suggests that increased ploidy of
the neoplastic epithelium, in genera!, does not affect receptor
dosage. This interpretation is consistent with our observation
that cytoplasmic and nuclear androgen receptor contents of
carcinomatous prostatic tissues are independent of relative carci
nomatous epithelial cell content (Chart 6). There also does not
appear to be a correlation between neoplastic epithelial cell
content and estrogen receptor content of breast carcinomas
(26).
These results would not appear to reflect a particular property
of early-stage disease represented by the radical prostatectomy
specimens. The mean and range of cytoplasmic and nuclear
androgen receptor content for lymph node métastasesof pros
tatic cancer from 3 untreated patients, respectively, were 935
(300 to 1585) and 415 (55 to 820) fmol per mg DNA.3 These
values are comparable to those determined for primary prostatic
carcinoma (Table 1). Because nodal prostatic carcinoma is de
void of noncarcinomatous tissue and surely contains polyploid
cells, these data for primary and metastatic prostatic carcinoma
suggest that androgen receptor dosage per cell in prostatic
carcinoma frequently may be greater than that of noncarcinom
atous prostate.
This interpretation is supported by the data of Charts 4 and 5.
When cytoplasmic androgen receptor content of paired noncar
cinomatous (benign) and carcinomatous tissues, from the same
prostate obtained at radical prostatectomy of 12 patients, was
evaluated, 42% (5 of 12) and 17% (2 of 12) of the carcinomatous
specimens, respectively, showed enhanced or unchanged recep
tor content relative to their paired benign specimen. The results
for nuclear androgen receptor content in these same paired
specimens plus an additional patient specimen for which cyto
plasmic data were lost, due to a mechanical failure, were 46%
(6 of 13) enhanced and 15% (2 of 13) unchanged.
3 S. A. Shain et al,, unpublished data.
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Androgen Receptors of Benign and Carcinomatous Prostate
Our data may help clarify 2 clinical observations. Commonly,
80% (for review, see Ref. 19) or more (1) of prostatic cancer
patients have at least limited positive response to ablative hor
monal therapy. In the current and other studies (comparable
comparative data have been obtained for radical prostatectomy
and needle biopsy specimens using a modified assay protocol4),
carcinomatous prostate specimens contain levels of cytoplasmic
and nuclear androgen receptors representative of the distribution
found in noncarcinomatous prostate. Therefore, the majority of
these specimens appears to contain functional receptors, and
their presence probably accounts for the initially favorable re
sponse to therapy. Similarly, the modest prognostic power of
androgen receptor analyses of carcinomatous tissues reported
by others (6, 25) may reflect the similarity of androgen receptor
content and distribution in benign and carcinomatous prostatic
tissue characteristic of cross-sectional analysis. Considering the
experience of others (6, 25) and the data of the current study,
we are inclined to believe that the determination of androgen
receptor content of carcinomatous prostatic tissues may provide
information of limited prognostic significance regarding response
(quality or interval) to ablative hormonal therapy. A more powerful
prognostic might be obtained by determination of receptor con
tent in matched specimens of carcinomatous and noncarcinom
atous prostatic tissue from the same gland. Those determina
tions may provide information concerning predicted altered hor
monal sensitivity of carcinomatous tissue relative to the individ
ual's benign tissue.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
ACKNOWLEDGMENTS
19.
We are deeply grateful to Ginny McGrath, R.N.. whose patience and dedication
made the close coordination between our surgical collaborators and ourselves
possible. We are indebted to the staffs of the Urology Services of The University
of Texas Health Science Center at San Antonio, the Audie L. Murphy Memorial
Veterans Administration Hospital, and the Wilford Hall United States Air Force
Medical Center, without whose participation this study would not have been
performed. We are grateful to Cheryl L. Boedeker, at Southwest Foundation, for
her assistance and guidance with the statistical analysis of the data.
21.
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