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and ß in Human Benign Prostatic Hyperplasia
Department of Urology (T.T.), The Japanese Red Cross Nagasaki Atomic Bomb Hospital, Nagasaki 852-8511; Department of Urology (D.A., H.K.), Nagasaki University School of Medicine, Nagasaki 852-8501; Department of Biochemistry (S.I., M.M.), Saitama Medical School, Saitama 350-0495; and Department of Histology and Cell Biology (T.T., Y.H., T.K.), Nagasaki University School of Medicine, Nagasaki 852-8523, Japan
Address all correspondence and requests for reprints to: Takehiko Koji, Ph.D., Department of Histology and Cell Biology, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: tkoji{at}net.nagasaki-u.ac.jp.
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and ß, has been implicated in the pathogenesis of benign and malignant human prostatic tumors, i.e. benign prostatic hyperplasia and prostate cancer, thought to originate from different zones of the prostate [the transition zone (TZ) and peripheral zone (PZ), respectively]. Here, we examined the cellular distribution of ER and ERß in human normal and hyperplastic prostate tissues, using in situ hybridization and immunohistochemistry. ER expression was restricted to stromal cells of PZ. In contrast, ERß was expressed in the stromal cells of PZ as well as TZ. ERß-positive epithelial cells were evenly distributed in PZ and TZ of the prostate. Our results suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperplasia through ERß. |
Introduction |
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The prostate is absolutely dependent on androgens to maintain its size and secretory function (5). Although the androgen-dependency of the prostate gland has long been known, the role of estrogen in the prostate has been only recently recognized. In canine studies, castrated dogs showed regrowth and normal function after administration of exogenous androgens. When estrogens were added to the treatment protocol, the dogs developed glandular hyperplastic prostate, including an increase in total cell number (6). In other studies, pharmacological doses of estrogens induced a marked proliferative response of prostatic glandular epithelium (termed: squamous metaplasia) in a variety of mammals, including human (7).
Whereas serum estrogen levels are low in healthy men [approximately half the levels in nonpregnant women (8)], serum and intraprostatic estradiol levels (both absolute levels and those relative to testosterone) increase in men with age, accompanied by an increase in the prostate volume (9, 10, 11). In addition, patients with larger volumes of BPH tend to have high levels of serum estradiol (12). Therefore, the estrogen-dominant status in men after middle age has been implicated in the induction and progression of BPH (10). However, the molecular mechanism of estrogen action in the development of human BPH is largely unknown.
Estrogens require the presence of estrogen receptors (ERs) for their actions. ERs belong to a nuclear receptor superfamily of ligand-activated transcription factors; and, at present, two types of ERs (ER and ERß) have been characterized (13, 14, 15, 16). ER was known as ER before the discovery of ERß, and its distribution has been thoroughly investigated in various human organs, including prostate and endometrium, breast cancer cells, and ovarian interstitial cells, which contain mostly ER (17, 18, 19, 20). ER has been detected in stromal cells of human prostate, although the cellular localization of ER remains controversial. At present, estrogen is thought to act indirectly on glandular cell proliferation, through ER-positive stromal cells, in a paracrine manner (21).
ERß has been recently cloned in the rat prostate and human testis (15, 16). ER and ERß share very high amino acid homology in the DNA binding domain, at 96%, but only show 53% homology in the ligand binding domain, as reported previously (22). The distribution of ER and ERß is variable, depending on tissues. In human, the testis contains mostly ERß, and this subtype is also present in a variety of tissues, including kidney, interstitial mucosa, lung parenchyma, bone marrow, bone, brain, endothelial cells, and prostate gland (23). Although the biological action of ERß in human prostate remains to be clarified, ERß knockout mice develop prostatic hyperplasia with aging, suggesting that ERß may play an important role in the development of BPH (24, 25). At present, however, there are conflicting reports on the cellular localization of ERß in human prostate. Enmark et al. (26) and Bonkhoff et al. (27) demonstrated that ERß expression was only marginal or absent in human prostate. On the other hand, using immunohistochemistry (IHC), Royuela et al. (19) reported that ERß was significantly expressed and localized only in the nuclei of the basal cells, whereas others detected a similar expression in the nuclei of stromal cells as well as the basal cells and also the cytoplasm of glandular epithelial cells by IHC (20, 28). Considering that the results of IHC are often influenced by the stability of the epitope and fixation procedure, analysis of ERß transcript by in situ hybridization (ISH) would be appropriate to resolve the controversy.
According to zonal anatomy described by McNeal et al. (29, 30), all BPH nodules and most PC foci arise in the transition zone (TZ) and the peripheral zone (PZ). To our knowledge, there are no studies that have examined the zonal differences, if any, in the expression of ER and ERß and whether such difference may reflect the pathogenesis of these prostatic diseases. In the present study, we first examined the cellular distribution of ERß mRNA and protein in normal human prostate tissues, using nonradioactive ISH and IHC, respectively. The antibody for ERß was raised by immunizing rabbits with a synthetic peptide of a part of the C-terminal domain of human ERß (22), and the specificity of this antibody was confirmed by Western blot analysis. We then investigated the expression of ER and ERß in human BPH tissues, by IHC, focusing on the difference between PZ and TZ. Our results revealed a discrete cellular distribution of ERs and that such distribution varied between the TZ and PZ, suggesting that the differential expression of ER and ERß may be involved in the pathogenesis of prostatic diseases, especially BPH. Our results also indicated that the zone-dependent staining for ER and ERß may explain, at least partly, the discrepancy for the distribution of ERs.
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Materials and Methods |
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DAB (3,3'-diaminobenzidine/4HCl) was purchased from Dojin Chemical Co. (Kumamoto, Japan). SDS-PAGE was purchased from Daiichi Pure Chemicals Company Ltd. (Tokyo, Japan). Immobilon, polyvinylidene difluoride membranes, was purchased from Millipore Corp. (Bedford, MA). The enhanced chemiluminescence system was purchased from Amersham International (Buckinghamshire, UK). Yeast tRNA, salmon testicular DNA, BSA, Brij 35, Tween 20, and 3-aminopropyltriethoxysilane were purchased from Sigma (St. Louis, MO). Formamide was purchased from Nacalai Tesque (Kyoto, Japan).
Antibodies
Antiserum against human ERß was obtained from a rabbit immunized with this peptide conjugated to keyhole limpet hemocyanin, as described previously (31). The synthetic oligopeptide sequence (511-CSPAEDSKSKEGSQNPQSQ-530) corresponding to the C-terminal amino acid residues of human ERß (22) was selected. When the titer of antibody reached a plateau, the entire peripheral blood was drawn, and the serum was separated. The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of Nagasaki University School of Medicine.
Mouse monoclonal antihuman ER IgG1 (1D5), normal goat serum, and normal rabbit serum were purchased from DAKO Corp. (Glostrup, Denmark). Mouse monoclonal antihuman androgen receptor (AR) IgG1 (NCL-AR-318) was purchased from Novocastra Laboratories (Newcastle, UK). Horseradish peroxidase (HRP)-conjugated goat antirabbit IgG F(ab')2 was purchased from MBL (Nagoya, Japan). HRP-conjugated goat antimouse IgG F(ab')2 was purchased from Chemicon International (Temecula, CA). Normal goat IgG and normal mouse IgG were purchased from Sigma. HRP-conjugated mouse monoclonal anti-T-T IgG was from Kyowa Medex (Tokyo, Japan).
All other reagents used in this study were from Wako Pure Chemical Industries Ltd. (Osaka, Japan) and were of analytical grade.
Tissue collection and preparation
Prostate tissues were obtained from 16 patients: 10 prostatic needle biopsy specimens (age, 55–75 yr) and 6 radical cystoprostatectomized prostates (age, 56–67 yr) from patients with primary muscle-invasive bladder cancer. Eleven of these tissues were diagnosed clinically and histopathologically as BPH, whereas the remaining 5 were normal. All specimens were obtained from patients at the Department of Urology, Nagasaki Atomic Bomb Hospital, in 2001. None of the patients had received any treatment before tissue sampling. The specimens of needle prostatic biopsies were obtained by the transperineal approach, under the guidance of transrectal ultrasonography. On the other hand, the samples of PZ or TZ were also taken from radical cystoprostatectomy, under direct vision. Some sections from all specimens were stained with hematoxylin and eosin for pathological examination to confirm the absence of PC and prostatic intraepithelial neoplasia.
For Western blot analysis, prostate tissue specimens (obtained from radical cystoprostatectomy) and human testis (obtained from patients with orchiectomy) for PC treatment were cut into several small pieces and rapidly frozen in liquid nitrogen and later used for the extraction of protein. For IHC, all prostatic samples were fixed with 10% neutral buffered formalin and embedded in paraffin using a standard procedure. The specimens were cut serially into 5-µm-thick sections and mounted on 3-aminopropyltriethoxysilane-coated glass slides.
IHC for ER, ERß, and AR
We used indirect enzyme-IHC for detection of ER, ERß, and AR. For IHC of ERß, paraffin sections were dewaxed with toluene and rehydrated by serial graded ethanol solutions. Then the sections were microwaved at 95 C for 20 min in 10 mM citrate buffer (pH 6.0). The following protocol was essentially similar to that previously established for rabbit polyclonal antibody (31). Briefly, after washing the sections with PBS, endogenous peroxidase activity was inhibited by immersing the slides in 0.3% H2O2 in methanol for 30 min. After the slides were washed with PBS again, they were preincubated with 10% normal goat serum and 1% BSA in PBS for 1 h to reduce nonspecific binding of antibodies. Then, the sections were reacted overnight with anti-ERß antiserum at a dilution of 1:400. After washing with 0.075% Brij 35 in PBS and rinsing with PBS, the sections were incubated with HRP-labeled goat antirabbit IgG F(ab')2 at a 1:200 dilution for 1 h. After washing with 0.075% Brij 35 in PBS and rinsing with PBS, the sites of HRP were visualized by DAB and H2O2. The sections were counterstained with Mayer’s hematoxylin. As a control, some sections were reacted with normal rabbit serum instead of the specific antiserum, at the same concentration.
For IHC of ER and AR, paraffin sections were processed in a manner similar to that described above. After preincubation with 500 µg/ml normal goat IgG and 1% BSA in PBS for 1 h, the sections were reacted with mouse monoclonal anti-ER IgG1 at a dilution of 1:200 and anti-AR IgG1 at a dilution of 1:50 overnight. After washing with 0.075% Brij 35 in PBS and rinsing with PBS, sections were incubated with HRP-labeled goat antimouse IgG F(ab')2 at a dilution 1:100 for 1 h. After washing in 0.075% Brij 35 in PBS and rinsing in PBS, the sites of HRP were visualized with DAB and H2O2 and then counterstained with Mayer’s hematoxylin. As a negative control, some sections were reacted with normal mouse IgG instead of the specific primary antibody, at the same concentration.
The frequency of positive cells for ERß, ER, and AR was graded as negative (-), occasionally positive (+), often positive (++), and abundantly positive (+++), relative to the background staining with normal rabbit serum or normal mouse IgG.
To confirm the zonal difference of ERß expression in the stroma of BPH specimens, the proportion of ERß-positive cells in the stroma of both PZ and TZ was calculated by counting at least 1000 cells at x400 magnification. A computer software package, StatView 4.5 (Abacus Concepts, Inc., Berkeley, CA), was used for statistical analysis. Data were expressed as mean ± SD. The difference in the proportion of ERß-positive stromal cells between two prostatic zones was examined using the Mann-Whitney U test. A P value less than 0.05 indicated statistical significance.
Western blot analysis of ERß
The frozen tissues were thawed and homogenized with a Polytron tissue homogenizer (Kinematica AG, Switzerland) in the lysis buffer consisting of 20 mM Tris-HCl (pH 7.4), 5 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, 2 µg/ml leupeptin, 10% glycerol, and 1% Triton X-100 on ice. After homogenization and centrifugation at 15,000 rpm for 30 min at 4 C, the supernatant was collected and then stored at -80 C.
Before Western blot analysis, the protein concentration was determined by the method of Bradford (32) using BSA as a standard. Then, an aliquot (10 µg) of the lysates was mixed with the loading buffer [consisting of 250 mM Tris-HCl (pH 6.8), 30% glycerol, 0.01% bromophenol blue, 2% SDS and 10% 2-mercaptoethanol], boiled for 5 min, and separated by SDS-PAGE with 4–20% gradient gel. After electrophoretic transfer onto polyvinylidene difluoride membranes, the membranes were incubated with PBS containing 5% nonfat dry milk and 5% BSA, to reduce nonspecific binding of antibodies for 1 h. Then the membranes were reacted overnight with anti-ERß antiserum at a dilution of 1:2000. After washing with 0.2% Tween 20 in PBS, the membranes were reacted with HRP-conjugated goat antirabbit IgG F(ab')2 at a dilution 1:3000 for 1 h. Finally, after washing with 0.2% Tween 20 in PBS, the bands were visualized by an enhanced chemiluminescence system.
Preparation of oligo-DNA probes for ERß
A 45-base sequence complementary to ERß mRNA (nucleotide no. 861–905) was selected. These antisense and sense sequences were synthesized together with two and three TTA repeats, at the 5'- and 3'-ends of sequences, and used as probes after haptenization with T-T dimer, as detailed previously (33). The sequences of antisense and sense probes used in this study were 5'-TTATTACACTAGCTGCTCGGGGCTCAGGGCGTCCAGCAGCAGCTCCCGCACATTATTATT-3' and 5'-T-TATTAGTGCGGGAGCTGCTGCTGGACGCCCTGAGCCCCGAGCA-GCTAGTGATTATTATT-3', respectively. A computer-assisted search of GenBank of the above antisense sequences, as well as sense sequences, showed no significant homology with any known sequences. The T-T dimer was introduced into oligo-DNAs by UV irradiation (254 nm) using a dose of 12,000 J/m2. The generation of T-T dimer was verified immunochemically using a mouse monoclonal anti-T-T IgG.
Dot-blot hybridization
Unless otherwise specified, all procedures were conducted at room temperature (20–25 C) throughout the experiment. Two-microfilter drops of the sense oligo-DNA solution were pipetted onto nitrocellulose membranes that had been pretreated with 20x standard saline citrate (SSC) [1x SCC; 0.015 M sodium citrate (pH 7.0) supplemented with 0.15 M sodium chloride] in series of spots at 1 pg to 10 ng/spot. The procedure of dot-blot hybridization has been described previously (34). Briefly, after air-drying, the filters were baked at 80 C for 2 h and incubated at 37 C for 2 h with prehybridization medium. The membranes were hybridized overnight at 37 C with 1 µg/ml T-T-dimerized oligo-DNA probe in hybridization medium. After hybridization, the membranes were immersed for 1 h in a blocking solution that contained 5% BSA, 500 µg/ml normal mouse IgG, 100 µg/ml yeast tRNA, and 100 µg/ml salmon testicular DNA in PBS. The reaction with HRP-linked mouse monoclonal anti-(T-T dimer) IgG at a 1:80 dilution was conducted at least for 3 h. The membranes were then washed with 0.075% Brij 35 in PBS for 1 h, and the sites of HRP were visualized using a chromogen solution containing DAB, H2O2, CoCl2, and NiSO4(NH4)2SO4 (35).
ISH for ERß
Nonradioactive ISH was performed according to the method described previously (33, 34). Briefly, sections were deparaffinized and rehydrated using standard procedures. This was followed by treatment with 0.3% H2O2 in methanol for 15 min to inhibit endogenous peroxidase activity, 0.2 N HCl for 20 min and 100 µg/ml proteinase K at 37 C for 15 min. After postfixation with 4% paraformaldehyde in PBS for 5 min, the sections were immersed in 2 mg/ml glycine in PBS for 30 min and kept in 40% deionized formamide in 4x SSC until used for hybridization. Hybridization was carried out for 12 h at 37 C with 2 µg/ml T-T-dimerized antisense oligo-DNA for ERß dissolved in the hybridization medium as described above. Then, the slides were washed with 50% formamide in 2x SSC, followed by 2x SSC. The signals were detected immunohistochemically, as described above. To evaluate the specificity of ERß mRNA signal, consecutive tissue sections were hybridized with T-T-dimerized ERß sense oligo-DNA as a negative control. Furthermore, the integrity of tissue RNA was assessed with T-T-dimerized 28S rRNA complementary probe (36).
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, ERß, and AR in hyperplastic prostates
We presented here the results of a typical case with BPH or its PZ normal part (Figs. 1
and 2). The histological examinations revealed epithelial hyperplasia of TZ and normal appearance of PZ (Figs. 1A and 2A).
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was consistently detected in the nuclei of stromal cells. However, ER-positive stromal cells were predominantly observed in PZ, but not in TZ, in normal and BPH tissues (Figs. 1B
and 2B). Thus, there was a clear difference in ER expression patterns between PZ and TZ, where the epithelial cells, basal cells, endothelial cells, and vascular smooth muscle cells were all negative for ER.
On the other hand, a moderate staining for ERß was detected in the nuclei of some but not all, epithelial and stromal cells, whereas it was strong in the nuclei of basal cells in normal and hyperplastic tissues, as shown in Figs. 1C and 2C. Interestingly, it should be noted that the staining for ERß in the glandular epithelial cells was found in the perinuclear as well as nuclear regions. The difference in the staining intensity for ERß between TZ and PZ was found in the stromal cells but not in the epithelial cells. The signal for ERß in the stromal cells of PZ is stronger than that of TZ. Although there was no difference in the cellular localization of ERß between PZ and TZ in BPH tissues, the number of ERß-positive cells was clearly less in the stroma of TZ than that of PZ. Quantitative analysis showed that the percentage of ERß-positive stromal cells in PZ (74.9 ± 9.0%) was significantly higher than in TZ (22.7 ± 8.9%, P < 0.0001, Mann-Whitney U test), whereas there was no difference in the percentages of ERß-positive cells of both glandular epithelial cells and basal cells between PZ and TZ.
In contrast, AR was consistently found in the nuclei of glandular epithelial cells, as well as in many stromal cells and some basal cells. Also, the nuclear staining in the basal cells was less intense than that of glandular epithelial cells. There was no difference in the expression of AR between PZ and TZ in BPH tissues, as shown in Figs. 1D and 2D. In addition, there was no significant variation in the expression of ER, ERß, and AR among BPH specimens, as summarized in Table 1.
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, E and F; and 2, E and F). Evaluation of specificity of immunohistochemical results with anti-ERß antiserum
Western blot analysis of ERß.
To confirm the specificity of the newly raised antiserum for human ERß, we performed Western blotting, using the lysate from human testis (lane 1, Fig. 3), which is known to express ERß (16). As shown in Fig. 3, a band of approximately 60 kDa was detected with the ERß antiserum. When the lysates from normal prostate tissues were analyzed by the ERß antiserum (lane 2), we also detected at least three bands (approximately 60-, 57-, and 53-kDa). The results may indicate the presence of several ERß splicing isoforms that have been found in the human prostate (22, 37). When the antiserum was replaced with normal rabbit serum, no bands were observed (lane 3).
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, when ERß sense oligo-DNA, fixed onto a nitrocellulose membrane at various amounts, was hybridized with T-T-dimerized ERß antisense oligo-DNA or T-T-dimerized ERß sense oligo-DNA, as little as 1 pg ERß sense DNA was detected with the antisense probe, but no signal was detected with the sense oligo-DNA. These results indicated that the antisense probe synthesized in our laboratory was specific, with adequate sensitivity to be useful in ISH studies.
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), and the staining for 28S rRNA was detected in the cytoplasm area as well as nucleoli, as shown in Fig. 5B. Further analysis of ERß mRNA expression in normal and hyperplastic prostate showed strong expression of ERß mRNA in most of the glandular epithelial cells, basal cells, and some stromal cells and that such staining pattern was not influenced anatomically, i.e. TZ and PZ. The signal for ERß mRNA was localized to the perinuclear area of the cytoplasm (Fig. 5C). The cellular distribution of the signal for ERß mRNA seemed to be essentially similar to that of ERß protein by IHC. As a negative control, adjacent sections were hybridized with the T-T-dimerized ERß sense oligo-DNA probe, resulting in no staining (Fig. 5D).
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Discussion |
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and ERß in human normal and hyperplastic prostates, and we found that ER was expressed only in the stromal cells of PZ but not of TZ. In contrast, ERß expression was detected in a wide variety of prostate cells, including glandular epithelial cells, basal cells, and stromal cells; and more importantly, the proportion of ERß-positive cells was significantly higher in the stroma of PZ than that of TZ. Considering that BPH nodules develop from the TZ, these results seem to indicate that ERß, rather than ER, may be preferentially involved in the pathogenesis of BPH.
During the past decade, conflicting results were reported regarding the localization of ER in human prostate tissue. In fact, a number of investigators, including our group, found both ER mRNA and its protein in stromal cells only (18, 19), whereas other groups found ER protein in some basal epithelial cells as well as stromal cells (17, 20, 27). Such discrepancies are poorly understood and are considered to be attributable to methodological differences. The present findings of zonal distribution of ER in human prostate offer an alternative explanation for the discrepancies; ER could not be detected in BPH specimens that were removed from TZ by open prostatectomy, whereas specimens of PC were positive for ER expression.
In the present study, we also investigated the expression of ERß in human prostate tissues by IHC and ISH, and we found differences in the percentages of ERß-positive cells in the stroma between TZ and PZ. These results contradict those of Leav et al. (20), who recently reported the lack of difference in ERß expression among central zone, TZ, and PZ. Although the reason for the discrepancy is not known at present, the roles of ERß-positive stromal cells in TZ should be of interest for a better understanding of the pathogenesis of BPH.
In a variety of tissues, including prostate gland, estrogens were thought to act on the induction of glandular epithelial cell proliferation, through ER-positive stromal cells, in a paracrine fashion (23). However, we could not find ER expression in the TZ, where BPH nodules develop. In addition, it is now known that there was no prostatic abnormality in ER knockout mice (38), and there was also no special mention of clinical features related to prostatic hyperplasia in a patient reported to lack functional ER (39). Therefore, we favor the notion that ER may not be involved in the pathogenesis of human BPH. On the other hand, ER expression was restricted to the stromal cells of PZ, which is supposed to be the origin site of PC. In addition, ER was localized in the nuclei of both many cancer cells and its surrounding stromal cells in PC tissues (18, 19, 20, 27, 40). Considering that estrogens are involved in cancer development, by stimulation of cell proliferation, in a variety of tumors, including PC (41), ER (rather than ERß) may be also implicated in both development and progression of PC (26, 42).
Moreover, the finding that ERß knockout mice develop prostatic hyperplasia with aging strongly indicates that ERß may play a negative role in the regulation of glandular epithelial cell proliferation in the prostate (24, 43). In fact, ERß is abundantly expressed in the glandular cells and basal cells of hyperplastic tissues (19, 25); but to date, there is no report on the role of ERß in the growth of normal human prostate. In addition, the expression of ERß was reduced in high-grade dysplasia, compared with that of normal prostate gland and lower grade lesions, and the ERß -positive cells in human PC tissues decreased with tumor grading or was absent (20, 28). In addition, ERß expression was lost in most of the human PC specimens, because of the inactivation of the ERß gene through CpG methylation of the promoter region of this gene (44). Therefore, these findings seem to suggest that ERß may protect glandular epithelial cells against abnormal growth in human prostate (44, 45).
Interestingly, the strongest staining for ERß was observed in the basal cells, in accordance with the findings by Leav et al. (20). In fact, it has been noticed that the basal cells have quite different biological properties from those of the glandular epithelial cells, particularly with respect to proliferation potential and steroidogenesis, and may play a crucial role in the prostatic carcinogenesis (46, 47). Therefore, we speculate that the ERß-positive basal cells may directly modulate the growth of themselves by estrogen via ERß. Moreover, AR is expressed not only in the basal cells but also in both the stromal and glandular epithelial cells. Because the basal cell proliferation is supposed to be antagonized by the purported growth-inhibitory action of ERß expressed in basal cells as well as stromal cells (20, 24, 25), it may be stimulated through adjacent AR- and ER-positive cells. Therefore, we propose that the environment in the stroma of TZ, where ERß expression is low, may be favorable for cell proliferation and the development of BPH.
Finally, we have demonstrated, in the present study, a differential expression of ER and ERß between TZ and PZ of human hyperplastic prostate, suggesting that estrogen may play a crucial role in the pathogenesis of BPH through ERß. In addition, we propose that the environment in the stroma of TZ, where ERß expression is low, may be favorable for the cell proliferation and the development of BPH.
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Footnotes |
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Abbreviations: AR, Androgen receptor; BPH, benign prostatic hyperplasia; DAB, 3,3'-diaminobenzidine/4HCl; ER, estrogen receptor; HRP, horseradish peroxidase; IHC, immunohistochemistry; ISH, in situ hybridization; PC, prostate cancer; PZ, peripheral zone; SSC, standard saline citrate; TZ, transition zone.
Received July 5, 2002.
Accepted November 25, 2002.
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References |
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and ß in the normal, hyperplastic and carcinomatous human prostate. J Endocrinol 168:447–454[Abstract]
and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 159:79–92 in vivo and in vitro. Biochem Biophys Res Commun 243:122–126[CrossRef][Medline]
and ER-ß in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Res 60:3175–3182 and ß in rat pituitary gland detected by immunohistochemistry. Endocrinology 141:615–620 and ERß at AP1 sites. Science 277:1508–1510This article has been cited by other articles:
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  P. Alonso-Magdalena, C. Brossner, A. Reiner, G. Cheng, N. Sugiyama, M. Warner, and J.-A. Gustafsson A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia PNAS, February 24, 2009; 106(8): 2859 - 2863. [Abstract] [Full Text] [PDF]
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 C. K M Ho, J. Nanda, K. E Chapman, and F. K Habib Oestrogen and benign prostatic hyperplasia: effects on stromal cell proliferation and local formation from androgen J. Endocrinol., June 1, 2008; 197(3): 483 - 491. [Abstract] [Full Text] [PDF]
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 S. Ulziibat, K. Ejima, Y. Shibata, Y. Hishikawa, M. Kitajima, A. Fujishita, T. Ishimaru, and T. Koji Identification of estrogen receptor beta-positive intraepithelial lymphocytes and their possible roles in normal and tubal pregnancy oviducts Hum. Reprod., September 1, 2006; 21(9): 2281 - 2289. [Abstract] [Full Text] [PDF]
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 Y. Takase, M.-H. Levesque, V. Luu-The, M. El-Alfy, F. Labrie, and G. Pelletier Expression of Enzymes Involved in Estrogen Metabolism in Human Prostate J. Histochem. Cytochem., August 1, 2006; 54(8): 911 - 921. [Abstract] [Full Text] [PDF]
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 C. P. Cheung, S. Yu, K. B. Wong, L. W. Chan, F. M. M. Lai, X. Wang, M. Suetsugi, S. Chen, and F. L. Chan Expression and Functional Study of Estrogen Receptor-Related Receptors in Human Prostatic Cells and Tissues J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1830 - 1844. [Abstract] [Full Text] [PDF]
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