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Original Studies |
-Reductases in Human Breast Carcinoma: Possible Modulator of in Situ Androgenic Actions1
Department of Pathology, Tohoku University School of Medicine (T.S., A.D.D., J.-I.A., S.O., C.K., J.T., H.S.), and Department of Pathology, Tohoku University Hospital (N.A., T.M.), Sendai 980-8575, Japan
Address all correspondence and requests for reprints to: Takashi Suzuki, M.D., Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. E-mail: t-suzuki{at}patholo2.med.tohoku.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase types 1 and 2 was examined in human
breast carcinoma using immunohistochemistry and RT-PCR.
Immunoreactivity for 5-reductase isozymes was also correlated with
various clinicopathological parameters to examine possible local
regulatory mechanisms of sex steroids, including progesterone and
androgens, in human breast carcinoma tissues. Immunoreactivity for
5-reductase type 1 was detected in the cytoplasm and possibly in the
nuclear membrane of tumor cells in 35 of 60 invasive ductal carcinomas
(58%), and type 2 signal was detected in 9 of these 60 cases (15%).
The results from RT-PCR (n = 8) were consistent with those from
immunohistochemistry. A significant positive correlation was detected
between 5-reductase type 1 immunoreactivity and androgen and
progesterone receptor A or B labeling indexes, and immunoreactivities
of 5-reductase type 2, 17ß-hydroxysteroid dehydrogenase type 5, or
3ß-hydroxysteroid dehydrogenase, which recognizes both types I and
II. An inverse correlation was detected between 5-reductase type 1
immunoreactivity and tumor size, histological grade, or Ki-67 labeling
index. 5-Reductase type 2 immunoreactivity was significantly
correlated with 17ß-hydroxysteroid dehydrogenase type 5
immunoreactivity, but not with other parameters. This study suggests
that 5-reductase type 1 is mainly expressed in human breast
carcinoma, which may play an important role in the in
situ production and actions of the potent androgen,
5-dihydrotestosterone, including inhibition of cancer cell
proliferation, in hormone-dependent human breast carcinoma. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5-Reductases catalyze the conversion of testosterone to the
bioactive and potent androgen, 5-dihydrotestosterone (DHT), and
metabolize progesterone to 5-dihydroprogesterone (5DHP)
(11). Therefore, 5-reductase expression is an important
regulator of the local actions of androgens and progesterone. Two
isoforms of 5-reductase have been cloned and characterized in
mammals. The type 1 5-reductase is located on the distal short arm
of chromosome 5 (11) and is mainly expressed in the liver
and skin (12). Type 2 5-reductase is located in band
p23 of chromosome 2 (13) and is expressed in the liver,
prostate, seminal vesicle, and epididymis (12). Recently,
several selective inhibitors of 5-reductase isozymes
(e.g. MK-386 for type 1 and finasteride for
type 2) have been developed and used in the treatment of
androgen-dependent disorders, including skin and prostate pathologies
(14). Therefore, it is very important to examine the
expression of 5-reductase isozymes to obtain a better understanding
of the role of 5-reductase and its regulation in various human
tissues and their disorders. Enzymatic activity for 5-reductase has
been demonstrated in both breast cancer cell lines (15)
and breast cancer tissues themselves (16). 5-Reductase
isozymes are considered to play important roles as local regulators of
sex steroid actions in human breast carcinoma, similar to P450
aromatase, which is regulator of estrogen actions. However, the
expression of 5-reductase isozymes has not been examined in breast
carcinoma, and its biological significance remains unknown. Therefore,
in this study we examined the expression of 5-reductase type 1 and
type 2 in human breast carcinoma tissues using immunohistochemistry and
RT-PCR. In addition, we statistically correlated the immunoreactivity
of 5-reductase isozymes with various clinicopathological parameters
in 60 cases of human breast carcinoma to study the possible role of
5-reductases in hormone-dependent breast cancer.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sixty specimens of invasive ductal carcinoma of the breast were obtained from women who underwent mastectomy from 1984–1987 at the Department of Surgery, Tohoku University Hospital (Sendai, Japan). Their mean age was 50.9 yr (range, 27–78). All patients examined in this study received neither irradiation nor chemotherapy before surgery. The clinical data, including patient age, menopausal status, stage according to International Union Against Cancer TNM classification (1987), tumor size, and lymph node status, were retrieved from the charts of the patients. The histological grade of each specimen was evaluated by three of the authors (T.S., N.A., and T.M.), based on the modified method of Bloom and Richardson (17) according to Elston and Ellis (18). The mean follow-up time was 107 months (range, 15–155). Disease-free survival data were available for all patients. All specimens were fixed with 10% formalin and embedded in paraffin wax at the Department of Pathology, Tohoku University Hospital.
Antibodies
5-Reductase type 1 and type 2 antibodies were rabbit
polyclonal antibodies against a synthesized peptide corresponding to
amino acids 232–256 for 5-reductase type 1 (12) and
amino acids 227–251 for 5-reductase type 2 (12),
respectively. These antibodies were provided by Dr. D. W. Russell
(University of Texas Southwestern Medical Center, Dallas, TX). The
polyclonal antibody for 17ß-hydroxysteroid dehydrogenase type 5
(17ßHSD5) was raised in rabbits against a synthetic peptide
corresponding to amino acids 297–320 for 17ßHSD5 (19)
and was provided by Dr. V. Luu-The (Laval University Hospital
Center, Quebec, Canada). The characterization of these three
antibodies was confirmed by Western blotting (12, 19), and
use of antibodies for 5-reductase type 2 (20) and
17ßHSD type 5 (19) on immunohistochemistry has been
previously reported. Polyclonal antibody for 3ßHSD was provided by
Dr. J. I. Mason (University of Edinburgh, Edinburgh, UK). It was
raised in rabbits against purified human placental 3ßHSD
(21), and the immunoreactivity has also been demonstrated
in human adrenals (22), indicating that this antibody
detects both 3ßHSD types I and II (23). Monoclonal
antibodies for AR (AR441), two isoforms of PR [PR-A (hPRa7)
(24) and PR-B (hPRa2) (25)], ER (ER1D5), and
Ki-67 (MIB1) were purchased from DAKO Corp. (Carpinteria,
CA) NeoMarkers (Fremont, CA), NeoMarkers, Immunotech
(Marseilles, France), and Immunotech, respectively. Rabbit
polyclonal antibody for HER-2/neu (A0485) was obtained from
DAKO Corp.
Immunohistochemistry
Immunohistochemical analysis was performed employing the
streptavidin-biotin amplification method using a Histofine Kit
(Nichirei, Tokyo, Japan) and has been previously described in detail
(26). For immunostaining of AR, PR-A, PR-B, ER, Ki-67, and
HER-2/neu, the slides were heated in an autoclave at 120 C
for 5 min in citric acid buffer (2 mmol/L citric acid and 9 mmol/L
trisodium citrate dehydrate, pH 6.0) after deparaffinization for
antigen retrieval. The dilutions of primary antibodies used in our
study were as follows: 5-reductase type 1, 1:1000; 5-reductase
type 2, 1:1000; AR, 1:100; PR-A, 1:150; PR-B, 1:150; ER, 1:2;
17ßHSD5, 1:1000; 3ßHSD, 1:1000; Ki-67, 1:50; and
HER-2/neu, 1:200. The antigen-antibody complex was
visualized with 3,3'-diaminobenzidine solution [1 mmol/L
3,3'-diaminobenzidine, 50 mmol/L Tris-HCl buffer
(pH 7.6), and 0.006%
H2O2] and counterstained
with hematoxylin. Tissue sections of liver and prostate were used as
positive controls for 5-reductase type 1 and type 2, respectively
(12), and nonneoplastic breast tissue was used as a
positive control for 17ßHSD type 5 (19). As a negative
control, normal rabbit or mouse IgG was used instead of the primary
antibodies, and no specific immunoreactivity was detected in these
sections.
RT-PCR
RT-PCR analysis was performed on eight specimens of invasive
ductal carcinoma. Total ribonucleic acid (RNA) was extracted from
frozen breast carcinoma tissue samples using an RNeasy Total RNA
isolation kit (QIAGEN, Hilden, Germany). RNA
concentrations were determined spectrophotometrically. Total RNA (5
µg) was denatured at 70 C for 10 min and was reverse transcribed in
the presence of 25 ng/µl
oligo(deoxythymidine)12–18 primer (Life Technologies, Inc., Tokyo, Japan), 2.5 mmol/L
MgCl2, 0.5 mmol/L deoxy-NTPs, 10 mmol/L
dithiothreitol, and 10 U ribonuclease H- reverse
transcriptase (SuperScript II RT, Life Technologies, Inc.,
Tokyo, Japan) for 20 min at 23 C, 60 min at 42 C, and 15 min at 70 C.
Subsequently, 1 µL of the resulting complementary DNA (cDNA) was used
as a template for PCR. The primer sequences used in this study
(27, 28, 29, 30) are listed in Table 1
. PCR amplifications were performed in a
final volume of 50 µL in the presence of 20 mmol/L Tris-HCl (pH 8.4),
50 mmol/L KCl, 0.2 mmol/L deoxy-NTPs, 2 mmol/L
MgCl2, 0.8 µmol/L of each primer, and 2.5 U
Taq DNA polymerase (Life Technologies, Inc.).
An initial denaturing step of 95 C for 2 min was followed by 40 cycles
(AR and 5-reductase type 1 and type 2) and 30 cycles (ß-actin),
respectively, of 95 C for 1 min; 1-min annealing at 50 C
(5-reductase type 1), 60 C (5-reductase type 2), 56 C (AR), and
58 C (ß-actin); and a final extension for 2 min at 72 C. All PCR
cycling was performed on a PTC-200 Peltier Thermal Cycler DNA Engine
(MJ Research, Inc., Watertown, MA). After PCR, the
products were resolved on a 2% agarose ethidium bromide gel. Images
were captured with Polaroid (Hertfordshire, UK) film under UV
transillumination. In initial experiments, after amplification PCR
products were purified and subjected to direct sequencing (ABI PRISM
BigDye Terminator Cycle Sequencing Ready Reaction Kit and ABI Prism 310
Genetic Analyzer, Perkin-Elmer Corp. PE Applied Biosystems, Foster City, CA) to verify amplification of the
correct sequences. As a positive control, frozen tissues of liver were
used for 5-reductase type 1 and AR, and those of prostate were used
for 5-reductase type 2. Negative control experiments lacked the cDNA
substrate to check for the possibility of exogenous contaminant DNA. No
amplified products were observed under these conditions.
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For statistical analyses of 5-reductase type 1 and type 2,
17ßHSD type 5, 3ßHSD, and HER-2/neu immunoreactivity,
the carcinomas were classified into two groups (+, positive carcinoma
cells; and -, no immunoreactivity) by three of the authors (T.S.,
T.M., and N.A.) independently. Cases with discordant results among the
observers were reevaluated. Scoring of AR, PR-A, PR-B, ER, and Ki-67 in
carcinoma cells was performed on high power fields (x400) using a
standard light microscope. In each case, more than 500 carcinoma cells
were counted independently by these same three authors, and the
percentage of immunoreactivity, i.e. labeling index (LI),
was determined. In the present study interobserver differences were
less than 5%, and the mean of the three values was obtained.
Statistical analysis
Values for patient age, tumor size, and LIs for AR, PR-A, PR-B,
ER, and Ki-67 were presented as the mean ± 95% confidence
interval (95% CI), and associations between the immunoreactivity of
5-reductases and these parameters were evaluated using a Bonferroni
test. Statistical differences between immunoreactivity for
5-reductases and menopausal status, stage, lymph node status,
histological grade, and immunoreactivity for 17ßHSD5, 3ßHSD, and
HER-2/neu were evaluated in a cross-table using the
2 test. P < 0.05 was
considered significant. Overall and disease-free survival analyses were
calculated according to the Kaplan-Meier test. The statistical
significance of differences in the survival analyses was calculated
using the log-rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunoreactivity for 5-reductase type 1 and type 2 was detected
in the cytoplasm and possibly in the nuclear membrane of carcinoma
cells (Fig. 1, A and B). The number of
positive cases and percentages were 35 of 60 cases (58.3%) for
5-reductase type 1, and 9 of 60 cases (15.0%) for 5-reductase
type 2, respectively. Immunoreactivity for 5-reductase type 1 and
type 2 was focally detected in morphologically normal glandular
epithelia adjacent to the carcinoma. To examine the possible effects of
long-term storage of the samples on immunoreactivity of
5-reductases, we performed immunohistochemistry for 5-reductase
types 1 and 2 in 12 invasive ductal carcinomas collected within 1 yr.
Immunoreactivity for 5-reductase type 1 and type 2 was detected in 8
of 12 (66.7%) and 3 of 12 (25.0%), respectively.
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), PR-A, PR-B, and ER was detected in
the nuclei of carcinoma cells, and the number of positive cases and
percentages were 49 of 60 (81.7%), 33 of 60 (55%), 38 of 60 (63.3%),
and 51 of 60 (85.0%), respectively. Immunoreactivity for 17ßHSD type
5 was detected in cytoplasms of carcinoma cells (Fig. 1D) in 37 of 60
cases (61.7%) examined. Immunoreactivity for 17ßHSD5 was also
detected in the cytoplasms of morphologically normal glandular
epithelial cells and some stromal cells adjacent to the carcinoma, as
reported previously (19). 3ßHSD immunoreactivity was
detected in the cytoplasms of carcinoma cells in 32 cases (53.3%; Fig. 2). Ki-67 immunoreactivity was detected
in the nuclei of carcinoma cells as well as some stromal cells in all
cases examined. HER-2/neu immunoreactivity was detected in
membranes of carcinoma cells in 27 of 60 cases (45%) in this
study.
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As shown in Fig. 3, messenger RNA
(mRNA) expression for 5-reductase type 1 and type 2 and AR was
detected as a specific single band (308 bp for 5-reductase type 1,
315 bp for 5-reductase type 2, and 420 bp for AR) in eight of three
(100%), three of eight (37.5%), and eight of eight (100%) cases,
respectively. The results of RT-PCR analyses in each case were
consistent with those of immunohistochemistry.
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-reductases and clinicopathological
parameters
The results of correlation between 5-reductases and
clinicopathological parameters are summarized in Table
2. As shown in Table 2A, a significant
inverse correlation was detected between 5-reductase type 1
immunoreactivity and tumor size (P = 0.043) or
histological grade of the carcinoma tissue (P = 0.013).
There was, however, no significant correlation between 5-reductase
type 1 immunoreactivity and patient age, menopausal status, stage, or
lymph node status. 5-Reductase type 2 immunoreactivity was not
significantly correlated with any clinicopathological parameters
examined in this study (Table 2B).
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-reductases and steroid receptors and
enzymes
The results of correlation between 5-reductase type 1 and
immunohistochemical parameters are summarized in Table 3A. There was a strong correlation
between 5-reductase type 1 immunoreactivity and AR LI
(P = 0.0026). A significant positive correlation was
also detected between 5- reductase type 1 immunoreactivity and
5-reductase type 2 immunoreactivity (P = 0.030),
PR-A LI (P = 0.039), PR-B LI (P =
0.042), 17ßHSD type 5 immunoreactivity (P = 0.0034),
and 3ßHSD immunoreactivity (P = 0.023). There was a
significant inverse correlation between 5-reductase type 1
immunoreactivity and Ki-67 LI (P = 0.020). The results
of correlation between 5-reductase type 2 and these parameters above
are summarized in Table 3B. 5-Reductase type 2 immunoreactivity was
significantly correlated with 17ßHSD type 5 immunoreactivity
(P = 0.010), but other significant correlations were
not detected in this study.
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-reductases and prognosis
No significant correlation was detected between 5-
reductase type 1 or type 2 immunoreactivity and overall or
disease-free survival in the 60 invasive ductal carcinomas investigated
in this study.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase type 1 was
detected in carcinoma cells in 35 of 60 human breast carcinomas
(58.3%), whereas that of 5-reductase type 2 was detected in
carcinoma cells in 9 of 60 cases (15.0%) examined. Activity of
5-reductase has previously been demonstrated in various human breast
carcinoma cell lines (15, 31), and Wiebe et al.
(16) reported that 5-reductase activity was 4–8 times
elevated in breast cancer tissues compared with that in nontumorous
breast tissues. Results from our present study are consistent with
these previous reports and suggest that type 1 5-reductase is mainly
expressed in carcinoma cells of human breast carcinoma tissues.
Immunoreactivity for 5-reductase types 1 and 2 was detected in the
cytoplasm and possibly in the nuclear membrane in this study. These
findings are consistent with previous reports that describe both of
these antigens as being integral membrane proteins localized to the
endoplasmic reticulum and the contiguous nuclear membrane
(11). However, further investigations, including
ultrastructural immunohistochemistry, are required to study the precise
subcellular localization of 5-reductase type 1 and type 2 in human
breast carcinoma cells.
In this study 5-reductase type 1 immunoreactivity was significantly
correlated with AR LI (P = 0.0026), which suggests that
5-reductase type 1 plays an important role in the regulation of
local androgenic actions. Previously, Isola (8) reported
that 79% of breast carcinomas expressed AR, suggesting that androgenic
actions are present in human breast carcinoma tissues. Physiological
concentrations of potent androgens such as DHT were very low in normal
woman (32, 33, 34) and in breast cancer patients
(35). However, Recchione et al.
(36) demonstrated that DHT concentrations were
significantly higher (3-fold increase; P = 0.0001) in
breast cancer tissues than in plasma and suggested the possible local
production of DHT in human breast carcinoma tissues. Recently, 17ßHSD
type 5, which specifically catalyzes the reduction of androstenedione
to testosterone, was cloned by Dufort et al.
(37). 17ßHSD type 5 is expressed in various peripheral
tissues, including the breast (19), and El-Alfy
(38) proposed possible in situ production of
DHT from the inactive adrenal precursor dehydroepiandrosterone
(DHEA) by 3ßHSD (conversion from DHEA to
androstenedione), 17ßHSD type 5 (reduction of androstenedione to
testosterone), and 5-reductases (metabolism of testosterone to DHT)
in various peripheral tissues. Previous studies have reported the
presence of 3ßHSD activity in breast carcinoma tissues
(39) and that of 17ßHSD activity in breast carcinoma
cell lines (31) in addition to 5-reductase activity in
human breast carcinoma tissues (16). An
immunohistochemical study of 3ßHSD in breast carcinoma cells has been
previously reported by Sasano et al. (40), but
that of 17ßHSD type 5 or 5-reductases has not been examined. In
this study immunoreactivity for 3ßHSD and 17ßHSD type 5 was
detected in carcinoma cells in 32 (53.3%) and 37 (61.7%) of 60
invasive ductal carcinomas, respectively, and immunoreactivity for
5-reductase type 1 was correlated with that of 3ßHSD
(P = 0.023) or 17ßHSD type 5 (P =
0.0034) immunoreactivity. Therefore, the results of our study suggest
that DHT is locally produced by 3ßHSD, 17ßHSD type 5, and
5-reductase type 1 in carcinoma cells and acts on these cells
locally via AR in human breast carcinoma tissues.
There was a significant inverse correlation between 5-reductase type
1 immunoreactivity and Ki-67 LI (P = 0.020) or tumor
size (P = 0.043) in this study. Monoclonal antibody
Ki-67 has been demonstrated to recognize cells in all phases of the
cell cycle except the G0 (resting) phase
(41), and Ki-67 LI is well recognized to be a useful
factor to evaluate the proliferative activity of various neoplastic
tissues, including breast carcinoma (42). Previous
in vitro studies have demonstrated that DHT inhibited the
basal and estrogen-induced cell proliferation in human breast cancer
cell lines through actions on AR, and this effect occurred at
physiological concentrations (4, 6). Our present findings
are in good agreement with these previous in vitro studies
mentioned above and suggest that 5-reductase type 1 locally induces
DHT production and results in a relatively low proliferation rate in
human breast carcinoma. 5-Reductase type 1 immunoreactivity was also
inversely correlated with histological grade (P =
0.013). Therefore, breast carcinomas positive for 5-reductase type 1
are considered to be relatively well differentiated and may maintain
some hormonal regulatory mechanisms. Administration of androgens has
been reported to result in the regression of some cases of breast
carcinoma, but also to cause androgenic side-effects (5).
Therefore, induction of 5-reductase type 1 may be effective, with
fewer side-effects, in the treatment of breast carcinomas as one
possible endocrine therapy.
Recent studies have demonstrated that the bioactive estrogen,
estradiol, was produced locally in breast carcinoma tissues. P450
aromatase converts androstenedione to estrone and testosterone to
estradiol. Enzymatic activity of aromatase has been demonstrated in
human breast carcinoma tissues (43), and aromatase
immunolocalization has been reported in stromal cells of breast
carcinoma tissues (40). Immunoreactivity for 17ßHSD type
1, which catalyzes the conversion of estrone to estradiol, has been
reported in carcinoma cells in breast carcinoma tissues
(44, 45, 46) and has been correlated with ER LI
(46). AR-positive breast carcinomas are frequently
positive for ER (8), and thus, it is reasonable to observe
a strong correlation between AR and ER LIs (r = 0.400;
P = 0.0015) in this study. Therefore, 17ßHSD type 5
and 5-reductases may act to increase DHT production through
competition with aromatase of estrogen production in hormone-dependent
breast carcinomas (Fig. 4).
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DHP and 3-hydroxyprogesterone
(3-HP) by 5-reductase and 3-hydroxysteroid oxidoreductase,
respectively, and the ratio of 5DHP/3-HP was nearly 30-fold
higher in tumorous than in nontumorous breast tissues using enzymatic
assay. They also reported that 5DHP stimulated, whereas 3-HP
inhibited, the proliferation and detachment of breast cell lines
in vitro. These previous findings above suggest that
5-reductase may decrease the biological actions of progesterone,
including the antiproliferative effect. However, in this study,
5-reductase type 1 immunoreactivity was correlated with PR-A and
PR-B LIs (P = 0.039 and P = 0.042,
respectively), and inversely correlated with Ki-67 LI
(P = 0.020) or tumor size (P = 0.043).
Therefore, evidence of regulation of progesterone action by
5-reductases could not be verified. This may partly be due to the
concentration of progesterone being lower than that of DHT, which may
be locally produced in human breast carcinoma tissues. However, studies
are required to confirm these speculations.
In summary, we demonstrated that 5-reductase type 1 is mainly
expressed in human breast carcinomas by immunohistochemistry and
RT-PCR. Immunoreactivity for 5-reductase type 1 was significantly
correlated with AR, PR-A or PR-B LI, and 5-reductase type 2,
17ßHSD type 5, or 3ßHSD immunoreactivity and was inversely
correlated with tumor size, histological grade, or Ki-67 LI. Our
present data suggest that 5-reductase type 1 plays an important role
in the regulation of in situ DHT production and actions,
including the inhibition of cancer cell proliferation, in
hormone-dependent breast carcinomas.
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Acknowledgments |
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Footnotes |
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Received October 3, 2000.
Revised January 9, 2001.
Accepted January 24, 2001.
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 C. H. van Gils, N. C. Onland-Moret, M. Roest, P. A. H. van Noord, and P. H. M. Peeters The V89L Polymorphism in the 5-{alpha}-Reductase Type 2 Gene and Risk of Breast Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1194 - 1199. [Abstract] [Full Text]
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 J.-L. Carsol, S. Gingras, and J. Simard Synergistic Action of Prolactin (PRL) and Androgen on PRL-Inducible Protein Gene Expression in Human Breast Cancer Cells: A Unique Model for Functional Cooperation between Signal Transducer and Activator of Transcription-5 and Androgen Receptor Mol. Endocrinol., July 1, 2002; 16(7): 1696 - 1710. [Abstract] [Full Text] [PDF]
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