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Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Address all correspondence and requests for reprints to: Tanri Shiozawa, M.D., Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: tanri{at}hsp.md.shinshu-u.ac.jp.
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Abstract |
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Introduction |
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Recent research into steroid-receptor-related signaling identified a group of molecules termed as steroid receptor cofactors (11, 12, 13). These factors bind to steroid receptors in a ligand-dependent fashion, and the receptor-bound cofactors then bind to the basal transcriptional machineries of the target genes, resulting in the transcription. Thus, the steroid receptor cofactors are important molecules intervening between the receptors and target genes and are now functionally divided into two subclasses, i.e. coactivators and corepressors. The former stimulates, and the latter suppresses, the transcription of target genes. In the human endometrium, however, there have been no systematic examinations on the expression and localization of these coactivators and corepressors, and their involvement in cell growth has not been analyzed. In the present study, therefore, we selected two coactivators [SRC-1 (steroid receptor coactivator-1) (14, 15) and p300/CBP (CREB-binding protein, a substantial homolog of p300) (16, 17)] and two corepressors [NCoR (nuclear receptor corepressor) (18) and SMRT (silencing mediator for retinoid and thyroid-hormone receptors) (19)], because p300/CBP and SRC-1 are crucial molecules in the first step of the transcription (20), and NCoR and SMRT are reported to recruit ER/PR (21, 22). The expression of these molecules was immunohistochemically examined and compared with that of ER, PR, and proliferation marker Ki-67. In addition, to evaluate the functional complex-formation between the coactivators and the receptors, binding of SRC-1 and p300/CBP to ER or PR was examined by immunoprecipitation.
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Subjects and Methods |
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Histological materials. Fifty normal endometrial tissue specimens were obtained from 50 women (age, 35–45 yr), all of whom had regular menstrual cycles and a previous history of pregnancy. The tissue was extirpated, at the time of hysterectomy, under a diagnosis of uterine myoma or cervical carcinoma in situ. The tissue was used with the approval of the Ethical Committee of Shinshu University, Japan, after obtaining written consent from the patients. Each specimen was immediately fixed in 10% phosphate-buffered formalin for 24 h and embedded in paraffin. Serial sections of 3-µm thickness were made and provided for hematoxylin and eosin staining and immunostaining. Histological diagnosis and endometrial dating (23) were performed on a hematoxylin and eosin-stained slide. Of the 50 endometrial tissue specimens, 10 were in the early proliferative phase (d 6–9), 10 were in the late proliferative phase (d 10–14), 12 in the early secretory phase (d 15–18), 9 in the midsecretory phase (d 19–22), and 9 in the late secretory phase (d 23–28).
Staining procedures.
Indirect immunostaining was performed using specific antibodies against SRC-1, p300/CBP, NCoR, and SMRT. An antibody for p300/CBP, which recognizes both p300 and CBP, was purchased from NeoMarkers (Fremont, CA). Antibodies for SRC-1 and NCoR were from Upstate Biotechnology, Inc. (Lake Placid, NY), and an anti-SMRT antibody was from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Anti-Ki-67, anti-ER antibody that specifically recognizes ER-
, and anti-PR antibody that recognizes both PR-A and PR-B were obtained from Immunotech (Marseille, France). Each immunohistochemical staining was performed using the avidin-biotin-peroxidase complex method with a Histofine SAB-PO detector kit (Nichierei Co., Tokyo, Japan). Briefly, after routine deparaffinization and rehydration, sections were treated with microwaves in a 0.01-M citrate buffer (pH 6.0) for 15 min. After blocking of endogenous peroxidase activity, the sections were then incubated with specific primary antibodies (diluted 1:100 with PBS/BSA) or control nonimmunized mouse or rabbit serum at 4 C overnight. After washing with PBS, biotinylated antimouse or rabbit IgG was applied for 30 min at room temperature. For negative control of the secondary antibody, biotinylated antirabbit or mouse IgG was applied for mouse or rabbit primary antibodies, respectively. After washing with PBS, peroxidase-conjugated streptoavidin solution was applied for 30 min and visualized by 0.05% 3'-3' diaminobenzidine. Counterstaining was performed lightly with hematoxylin.
Interpretation of immunohistochemical staining. The specific staining of each antibody was identified in the nucleus. All the control slides yielded negative staining. The positivity of each staining was also described as a positivity index (PI), which indicates the percentage of positive cells in 200 cells from 3 high-powered fields in each section. Because the cell proliferation is known to differ in the functional layer vs. in the basal layer of the endometrium, the PI of each factor was assessed in the respective layers. Statistical analysis for the PI comparison between menstrual phases was done with the Kruskal Wallis test and Sheffe’s test, whereas that between the functionalis and basalis was done with the Mann-Whitney U test. A tied P value less than 0.05 was considered significant.
Western blotting
To confirm the antigenic specificity of the antibodies used for immunostaining, Western blotting was performed as described previously (10). In brief, four fresh tissue specimens (two from the proliferative phase and two from the secretory phase) were homogenized and lysed in 0.5 ml of a cell lysis buffer consisting of 50 mM Tris-HCl (pH 8.0), 0.25 M NaCl, 0.5% NP-40, 1 mM PMSF (Sigma, St. Louis), 1 µg/ml aprotinin (Roche Molecular Biochemicals, Indianapolis, IN), 1 µg/ml leupeptin (Roche Molecular Biochemicals), and 20 µg/ml tosylphenylalanine chloromethylkeytone (Roche Molecular Biochemicals). The lysates were centrifuged at 13,000 x g for 20 min at 4 C, and the supernatants were stored at -70 C. Extracts equivalent to 50 µg total protein were separated on sodium dodecyl sulfate (SDS)-polyacrylamide gels (10% acrylamide). The proteins were then transferred to supported nitrocellulose membranes (Amersham International, Buckinghamshire, UK) by applying 20V for 180 min with a plate electrode apparatus (Semi Dry Blotter II; Ken En Tec, Copenhagen, Denmark). The filters were blocked for 1 h in Tris-buffered saline with Tween 20 (TBST) consisting of 0.2 M NaCl, 0.2% Tween 20, and 10 mM Tris (pH 7.4), containing 5% nonfat dry milk and 0.02% NaN3. Subsequently, the filters were incubated with antibodies against SRC-1, NCoR (Upstate Biotechnology, Inc.), p300/CBP (NeoMarkers), SMRT (Santa Cruz Biotechnology, Inc.), and ß-actin (for the loading control, AC-15; Biomakor, Rehovot, Israel) (each diluted 1:500) in TBST containing 5% milk, and then incubated in antimouse or rabbit IgG (1:1,000; Amersham International) in TBST containing 2% milk. The filters were washed several times with TBST after each step. The bound antibodies were detected with an enhanced chemiluminescence system (Amersham International).
Immunoprecipitation
Complex formation between coactivators and ER or PR was examined by immunoprecipitation using lysates obtained from the six normal endometrial tissues (each of three cases of the proliferative and secretory phases) and from two breast cancer cell lines, MCF-7 (purchased from American Type Culture Collection, Manassas, VA), in which the binding of ER with SRC-1 and p300/CBP was reported (17), and T-47D (American Type Culture Collection), in which the binding of PR with these coactivators were reported (24), for the positive controls. Briefly, 50 µg of the lysate were immunoprecipitated with 2 µl of the anti-SRC-1 or p300/CBP antibodies for 60 min at 4 C. These precipitates were collected for 1 h on protein G-agarose (Calbiochem, La Jolla, CA). After washing with a lysis buffer, precipitates were resuspended in a Laemmli SDS sample buffer and resolved on SDS-PAGE. The immunoprecipitated protein complexes were resolved and probed for immunoblots, to detect associated proteins, using antibodies against ER- and PR (A and B) (Immunotech). Binding of ER/PR to corepressors was not examined because the immunostaining of corepressors was focal and an appropriate positive control was not available.
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Results |
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. Representative immunostaining for the coactivators and that for the corepressors is shown in Figs. 1 and 2, respectively. The change in PI of each factor in the glandular and stromal cells is schematically demonstrated in Figs. 3 and 4. Results of Western blotting and immunoprecipitation are shown in Figs. 5 and 6, respectively.
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Expression of SRC-1.
The expression of SRC-1 was observed in the nucleus. In the functionalis, SRC-1-positive cells were diffusely observed in the proliferative phase (PI, 82.6 ± 13.7) (mean ± SD). However, the PI suddenly decreased in the early secretory phase and reached the lowest level in the late secretory phase (PI, 42.5 ± 29.2). In the functionalis, the PI in the proliferative phase was significantly higher than that of the mid (P = 0.023) and late (P = 0.008) secretory phases. There were no marked differences in PI between the functionalis and basalis throughout the menstrual cycle (Figs. 1
, A–C, and 3 and Table 1).
Expression of p300/CBP.
The immunoreactivity of p300/CBP was also observed in the nucleus. p300/CBP-positive cells were constantly observed throughout the menstrual phases. In the functionalis, the expression of p300/CBP was more frequently observed in the proliferative phase with the highest PI (89.1 ± 10.3), which gradually decreased during the secretory phase. The PI in the late secretory phase (65.0 ± 21.4) was significantly lower than that of the proliferative phase (P = 0.032). There were no marked differences in PI between the functionalis and basalis (Figs. 1, D–F, and 3 and Table 1).
Expression of NCoR.
NCoR expression was observed mainly in the nucleus and slightly in the cytoplasm. The nuclear staining of NCoR was observed in the proliferative phase, with a PI of 22.2 ± 22 in the functionalis. In contrast, the expression of NCoR was almost negligible in the secretory phase. The PI in the functionalis of the proliferative phase was higher than that in the basalis, with significant difference (P = 0.005) (Figs. 2, A–C, and 3 and Table 1).
Expression of SMRT.
SMRT expression was observed both in the nucleus and in the cytoplasm. Nuclear staining was observed throughout the menstrual cycle. However, SMRT-positive cells were observed only focally, and the PI in each menstrual cycle was very low. There were no marked differences in PI between the functionalis and basalis (Figs. 2, D–F, and 3 and Table 1).
Expression of ER, PR and Ki-67.
Positive staining with antibodies against ER-, PR (A and B), and Ki-67 in the glandular cells was observed mainly in the proliferative phase, and expression of these molecules decreased in the secretory phase (Fig. 3 and Table 1).
Immunohistochemistry for stromal cells
Expression of SRC-1. Endometrial stromal cells positive for SRC-1 were most frequently observed in the proliferative phase, and the PI was 85.9 ± 7.9 in the functionalis. The PI decreased drastically in the secretory phase, the lowest (39.5 ± 23.9) in the early secretory phase with significant difference (P = 0.041). There were no significant differences in PI between the functionalis and basalis.
Expression of p300/CBP. Stromal cells positive for p300/CBP were observed throughout the menstrual cycle, most frequently observed in the proliferative phase, with the PI of 75.0 ±12.4 in the functionalis. The PI slightly decreased in the secretory phase, with the lowest (43.8 ± 15.1) in the late secretory phase. The PI of the basalis tended to be higher than that of the functionalis but did not show significant difference.
Expression of NCoR. Stromal cells positive for NCoR were observed in the proliferative phase, with the PI of 44.0 ± 22.2 in the functionalis, which was significantly higher than that of 23.1 ± 21.1 in the basalis (P = 0.039). In the secretory phase, however, the expression of NCoR was negative both in the functionalis and basalis.
Expression of SMRT. Stromal cells positive for SMRT were most frequently observed in the proliferative phase; the PI in the basalis (11.3 ± 11.4) was slightly higher than in the functionalis (7.5 ± 12.0), although there was no statistical difference between the two layers. In the secretory phase, the PI of SMRT-positive cells was very low both in the functionalis and basalis.
Expression of ER, PR, and Ki-67.
Positive staining with antibodies against ER-, PR (A and B), and Ki-67 was observed throughout the menstrual phases, with predominance in the proliferative phase. The difference of PI of each factor between the proliferative and secretory phases was not marked, compared with that of the glandular cells (Fig. 3 and Table 1).
Western blotting
All the tissue samples showed a single band, with a molecular mass of 160 kDa for SRC-1, 300 kDa for p300/CBP, 250 kDa for NCoR, and 168 kDa for SMRT (Fig. 5). In SRC-1, two samples from the proliferative phase showed slightly stronger bands than those of the secretory phase. There was no apparent difference in the signal intensity for p300/CBP between the proliferative and secretory phases. With regard to NCoR and SMRT, band intensity was very weak. In NCoR, one sample obtained in the proliferative phase showed a band, but no bands were observed in other samples. In SMRT, all samples showed a single band, but there was no apparent difference of the band intensity between the proliferative and secretory phases.
Immunoprecipitation
Complex formation between coactivators and steroid receptors was examined by immunoprecipitation (Fig. 6). When the lysates were immunoprecipitated with the anti-SRC-1 antibody and then the precipitates were examined with an anti-ER- antibody, the bands were observed in tissues from the proliferative phase but not from the secretory phase. In contrast, complex formation between p300/CBP and ER was observed in the tissue samples of both proliferative and secretory phases.
When the lysates were immunoprecipitated with the anti-SRC-1 antibody and then the precipitates were examined with an anti-PR (A and B) antibody, no bands were observed irrespective of the menstrual phase. However, binding of p300/CBP to PR was observed in one tissue sample obtained from the secretory phase. All the positive controls using breast cancer cells showed positive complex formation.
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Discussion |
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was also confirmed in the tissue samples obtained from the proliferative phase. To our knowledge, this is the first report on the fluctuation of SRC-1 expression in the hormone-targeted tissues. Because the cyclic change of SRC-1 expression during the menstrual cycle resembled the expression pattern of ER, PR, and Ki-67, up- and down-regulation of SRC-1 may also be functionally involved in the estrogen-ER-induced events such as PR induction and the cell proliferation in the endometrium. SRC-1 has also been reported to associate with another receptor PR. Our study showed that the immunoreactivity for PR (A and B) in the endometrium is diffusely observed in both glandular and stromal cells in the proliferative phase, as reported previously (29, 30), and that in the secretory phase, PR expression is immediately down-regulated in the glandular cells, whereas it remains present in the stromal cells. In our immunoprecipitation experiment, however, binding of SRC-1 to PR was not shown in the samples of either proliferative or secretory phase. Glandular and stromal cells in the proliferative phase strongly express SRC-1 and PR, but the progesterone level is very low in this period. Because the binding of coactivator to the receptor is reportedly ligand dependent, absence of binding of SRC-1 to PR may be reasonable. In the secretory phase, PR expression is still present in the stromal cells, and progesterone-induced decidualization and PRL secretion in vitro have been reported to be mediated by SRC-1 (31). Absence of bands in the immunoprecipitation using the samples of secretory phase may be attributable to the sensitivity of immunoprecipitation used in this study, although the positive control using breast cancer cells expressing PR showed a definite band.
Another coactivator, p300/CBP, is characterized by the presence of SRC-1 binding site on C-terminus and histone acetyl transferase activity (32). p300/CBP has also been reported to associate with steroid receptors, including ER, PR, thyroid hormone receptors, and retinoid receptors (33). In the present study, the expression of p300/CBP was diffusely observed in the glandular and stromal cells throughout the menstrual cycle, although its positivity was slightly higher in the proliferative phase. In addition, the complex formation between p300/CBP and ER- was observed not only in the endometrial tissues of the proliferative phase but also in those of the secretory phase. This is in contrast with that between SRC-1 and ER. In the secretory phase, ER- expression is down-regulated, but still present, in the stromal cells. Therefore, our results in the secretory phase are considered to represent the complex formation between p300/CBP and ER- in the stromal cells. Furthermore, the complex formation between p300/CBP and PR was also noted in one sample of the secretory phase, when the stromal cells still express PR. These findings suggest that p300/CBP is a so-called housekeeping molecule, i.e. it is generally present in both glandular and stromal cells of the endometrium, irrespective of the menstrual phases, and that it binds to ER or PR when the respective ligand is available.
It has been known that both SRC-1 and p300/CBP bind each other and form huge complexes with the steroid receptors and also with the basal transcriptional machineries of the target genes in a ligand-dependent fashion (25). Although the target molecules existing downstream of the coactivators-ER complexes remain undetermined, molecules like the AP-1 protein, possessing an estrogen-responsive element, might be candidates (34). Such complex formation, including SRC-1 and p300/CBP, has been reported to be required for estrogen-induced growth of breast cancer cells (17). The present study demonstrated the expression of both SRC-1 and p300/CBP and their binding to the receptors in the human endometrium; and the most interesting result from our study was the difference of expression pattern between SRC-1 and p300/CBP, i.e. that the expression p300/CBP is relatively constant, whereas that of SRC-1 shows drastic change during the menstrual cycle. In addition, binding of SRC-1 with ER was observed in the proliferative phase but not in the secretory phase. These findings suggest that an unknown regulation mechanism for the SRC-1 expression during the menstrual cycle may exist and that the change in the expression and function of SRC-1 may be important in the modulation of estrogen-action in the endometrium. Further research is needed to clarify the regulation of cyclic change of the SRC-1 expression in the endometrium.
Our study also demonstrated the expression of corepressors NCoR and SMRT in the endometrium. These corepressors are structurally characterized by the presence of a repressor domain in the N terminus and a receptor domain on the C terminus (35, 36). NCoR and SMRT bind to nuclear receptors, such as thyroid hormone receptors and retinoid receptors, in the absence of the respective ligands, whereas they dissociate from the receptors when the ligands are bound, leading to gene transcription. In addition, the corepressors recruit histone deacetylase-1 (37), which inhibits gene transcription. Thus, ligand-unbound NCoR and SMRT are believed to suppress the transcription of target genes. In the present study, the expression of NCoR was noted in glandular and stromal cells in the proliferative phase. This was consistent with the data from Western blot analysis. Previous studies have revealed the possible interaction of NCoR with ER and PR (21, 22, 38). The NCoR-ER fusion protein has been reported to suppress the ER-mediated transcription of breast cancer cells (39). With regard to SMRT, similar involvement in the suppression of ER- or PR-mediated transcription has also been suggested. The human endometrium is composed of the two distinct layers, i.e. the functionalis and the basalis, the latter of which hardly responds to estrogen or progesterone. Therefore, we had expected the localization of these corepressors in the basalis. Paradoxically, the number of NCoR-positive cells was significantly larger in the functionalis than that in the basalis. However, because the distribution of cells expressing these corepressors was sporadic, the functional significance of the expression NCoR and SMRT in the human endometrium remains to be elucidated. In addition, endometrial differentiation in the secretory phase, such as secretory change of the glandular cells and decidualization of the stromal cells, induced by progesterone could not be explained by the change in the expression of coactivators and corepressors obtained in this study. Further analysis, including other classes of cofactors, is needed to clarify the steroid receptor-related signaling in the human endometrium.
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Acknowledgments |
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Footnotes |
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Abbreviations: CBP, CREB-binding protein; CREB, cAMP-response element binding protein; ER, estrogen receptor(s); NCoR, nuclear receptor corepressor; PI, positivity index; PR, progesterone receptor(s); SDS, sodium dodecyl sulfate; SMRT, silencing mediator for retinoid and thyroid hormone receptors; SRC, steroid receptor coactivator; TBST, Tris-buffered saline with Tween 20.
Received June 18, 2002.
Accepted October 28, 2002.
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