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Department of Molecular and Cellular Oncology (R.K.V., S.B., R.K.) and Department of Pathology (R.R.B.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Center for Biotechnology (J.-Å.G.), Karolinska Institute, Novum, S-14157 Huddinge, Sweden
Address all correspondence and requests for reprints to: Ratna K. Vadlamudi, Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70005. E-mail: rvadla{at}LSUHSC.edu; or Rakesh Kumar, Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Box 108, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: rkumar{at}mdanderson.org.
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and ERß and enhances their transcriptional responses. However, in endometrial cancer cells, endogenous PELP1 is also required for optimal ligand-mediated transcription and proliferation responses. PELP1 promoted a tamoxifen-mediated agonistic action in endometrial, but not in breast cancer cells. PELP1 expression and localization are widely deregulated in endometrial cancers. In addition, PELP1 and ERß were localized predominantly in the cytoplasm of high-grade endometrial tumors. Our results suggest that PELP1 plays an essential role in the proliferation of cancerous endometrial cells. |
Introduction |
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and ERß (4, 5). The ER subtypes share a similar modular structure but differ in function and expression and have isoform-specific effects on gene expression (6). Upon binding to E2, ligand-activated ERs bind to ER-responsive elements and modulate respective gene expression (genomic signaling) (7, 8). It is increasingly recognized that the biological actions of ERs result from both genomic and nongenomic signaling. For example, ERs participate in transcription-independent functions (nongenomic action) through activation of cytosolic signaling pathways, including the Src, MAPK, protein kinase C, and protein kinase B (AKT) pathways (4, 9, 10, 11).
The transcription functions of ERs are influenced by several coactivators (12, 13, 14). We recently cloned a novel ER-regulatory protein named proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) (15), also referred to as modulator of nongenomic activity of ER (MNAR) (16, 17, 18). PELP1 is abundantly expressed in a number of tissues, including the mammary gland and the endometrium (15). PELP1 plays a permissive role in E2-mediated cell cycle progression through its regulatory interactions with the retinoblastoma pathway (18). Although PELP1 is predominantly localized in the nucleus (15, 19), recent studies suggest that, under certain conditions, PELP1 could be localized in the cytoplasm of breast cancer cells (20), which may suggest that it contributes toward the nongenomic action of ERs in cancer cells.
The differential action of estrogen in the breast and endometrium depends on the tissue-specific expression of the ER isoform, coregulators, and availability of novel integrators (21, 22). Emerging data and the identification of novel ER cofactors with diverse functions are beginning to shed light on the complex events of E2-ER signaling. Until now, however, few studies have looked at the expression of several coactivators such as steroid receptor coactivator 1 (SRC1), CEBP binding protein (CBP), and amplified in breast cancer-1 (AIB1) and corepressors such as nuclear receptor corepressor (NCOR) in the benign and cancerous endometrium (23, 24, 25). Because of the increasing awareness of the potential contribution of nongenomic and extranuclear functions of ER, it is important to examine the status and localization of novel steroid receptor coactivators such as PELP1 to fully understand the mechanisms of E2 signaling in the endometrium. The aim of present study was to analyze the expression and the localization of novel ER coactivator in the benign and cancerous endometrium. In addition, we have also examined the relevance of PELP1 in endometrial cancer cell proliferation and its potential role in tamoxifen-mediated partial agonist action in the endometrium.
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Materials and Methods |
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Residual endometrial tissue was derived from hysterectomy surgical specimens submitted to the Department of Pathology, M. D. Anderson Cancer Center. The use of human residual tissues used in this study was approved by M. D. Anderson Cancer Center institutional human research committee (protocol no. Lab01–718). Formalin-fixed, paraffin-embedded sections (3-µm thickness) derived from six Proliferative phase endometrium, six secretory phase endometrium, and six inactive postmenopausal endometrium samples were examined. In addition, a tissue array containing 60 endometrial cancer samples [endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) grades 1, 2, and 3] was used for immunohistochemistry experiments. Frozen endometrial tissue (benign and malignant) was also derived from hysterectomy surgical specimens. All tissue classifications were verified by light microscopic examination of hematoxylin and eosin-stained slides by a gynecologic pathologist (R.R.B.). The benign endometrial samples used for this study were derived from hysterectomies for cervical squamous cell carcinoma, uterine leiomyomas, and dysfunctional uterine bleeding secondary to endometriosis. In addition, we were careful to check the clinical records for such patients, and we did not use benign endometrial samples from patients with a prior history of hormone use, radiation treatment, or chemotherapy.
Cell culture and reagents
The human endometrial Ishikawa cell line, a model of well-differentiated endometrial adenocarcinoma, was kindly provided by Dr. Bruce A. Lessey (University of North Carolina at Chapel Hill, NC) (26). The endometrial cancer cell line RL 95–2 and breast cancer cell lines MCF-7 and MDA-MB-231 were obtained from the American Type Culture Collection (Manassas, VA). All the cells were maintained in DMEM/nutrient mixture F-12 (1:1) supplemented with 10% fetal calf serum. Dextran-coated, charcoal-treated fetal calf serum (DCC serum) and antibodies against actin, vinculin, and E2 were purchased from Sigma Chemical Company (St. Louis, MO). Antibodies against ER (MS-750-S1) were purchased from NeoMarkers (Fremont, CA) and Upstate Biotechnology, Inc. (Lake Placid, NY). The chicken antihuman ERß 503 antibody and antihuman ERß antibody have been previously described (27). ER-specific ligand propyl-pyrazole-triol (PPT) and the ERß-specific ligand diarylpropionitrile (DPN) were purchased from TOCRIS (Ellisville, MO). ERß-specific monoclonal antibody purchased from Oncogene Research products (San Diego, CA) was used for ERß immunoprecipitation.
Immunohistochemistry and interpretation of immunoreactivity
For immunohistochemical detection of ER, ERß, and PELP1, formalin-fixed, paraffin-embedded endometrial sections were deparaffinized with xylene and rehydrated using graded ethanol. Sections were incubated in 0.3% hydrogen peroxide and methanol for 30 min to inactivate the endogenous peroxidase. The sections were then boiled for 10 min in 0.01 M citrate buffer and cooled for 30 min at room temperature to expose antigenic epitopes. The sections were blocked with 2% normal goat serum in 1% BSA and PBS for 30 min and then incubated overnight at room temperature with primary antibodies against ER, 1:50 dilution (NeoMarkers); chicken ERß 503, 1:100 dilution (27); and PELP1, 1:500 dilution (15). Primary antibodies were diluted in diluent buffer (2% normal goat serum, 1% BSA, and PBS). For ER and PELP1, the sections were washed three times with 0.05% Tween in PBS for 10 min; incubated with biotinylated secondary antibody, 1:100 dilution (Vector Laboratories, Inc. Burlingame, CA) for 1 h; and then washed three times with 0.05% Tween in PBS for 10 min; incubated with a streptavidin horseradish peroxidase reagent (Dako Corporation, Carpinteria, CA) for 15 min; and washed three times with 0.05% Tween in PBS for 10 min. For ERß, the sections were washed three times with 0.05% Tween in PBS for 10 min; incubated with a rabbit antichicken secondary antibody, 1:100 dilution (Sigma Chemical Company, St. Louis, MO) for 1 h; and then washed three times with 0.05% Tween in PBS for 10 min and three times with 0.05% Tween in PBS for 10 min. The sections were then developed with diaminobenzidine-H2O2 and counterstained with Mayer’s hematoxylin. For negative control, slides were incubated with nonspecific mouse IgG for ER; chicken IgG for ERß. For PELP1 slides, peptide-absorbed PELP1 antibody was used as a negative control. The specific staining of each antibody was assessed semiquantitatively using a four-point scale: 0 = no staining, 1 = mild staining, 2 = moderate staining, and 3 = intense staining. Staining pattern (cytoplasmic vs. nuclear), as well as cell compartment stained (glandular epithelial cells vs. endometrial stromal cells), was also examined.
Cell growth and reporter assays
For the cell growth assay, cells were grown in phenol red-free medium supplemented with 5% DCC serum for 48 h, and growth was stimulated with supplemental estrogen. The growth rate of the cells was measured by counting them in a Beckman Coulter Counter (Kendal, FL) (18). For reporter-gene transient transfections, estrogen response element (ERE)-luciferase (luc) reporter constructs were cotransfected with or without PELP1/MNAR, ER, and ERß or a control vector (0.5 µg each) using FuGENE 6 (Roche Diagnostics Corporation, Indianapolis, IN) according to the manufacturer’s instructions as previously described (15). Ishikawa cells cultured in DCC serum were cotransfected with 3XERE-luc reporter gene with or without the PELP1 expression vector. After 24 h, cells were treated with E2 (10–9 M), and ERE-luc reporter activation was measured after 16 h. The activity of the ß-galactosidase reporter was used to correct the transfection efficiencies.
Western and immunoprecipitation analysis
Total protein lysates from cancer cells and endometrial benign and tumor samples were prepared using radioimmunoprecipitation buffer as described (15). For Western analysis, 100 µg total cellular extract was analyzed using antibodies specific to PELP1, ER, and ERß. Actin was used as a loading control. For immunoprecipitation, a total of 2 mg protein/each sample was incubated with 1 µg of the respective antibody.
RNA interference
For PELP1 knockdown, siGenome SMARTpool [short interference RNA (siRNA)] duplexes were purchased from Dharmacon (Lafayette, CO). The catalogue number and targeted sequences are as follows: D-004463–01-ggaagaagaaggugaguuauu (PELP1 siRNA no. 1); D-004463–02-caagguguaugcgauauuauu (PELP1 siRNA no. 2); D-004463–03-ccacagagccugacuccuauu (PELP1 siRNA no. 3); D-004463–04-ggaaugaaggcuuguaugauu (PELP1 siRNA no. 4). The catalog number for the PELP1 SMART pool siRNA is D-001210–01-20. The catalog number for siControl nontargeting siRNA is D001210–01-20. The GenBank accession number used to design siRNA is NM_014389. siRNA transfections were performed using oligofectamine according to the manufacturer’s protocol (Qiagen, Valencia, CA). In the initial screen, we have checked all the four siRNA individually as well as the SMART pool of four siRNAs. Of all the four PELP1 siRNAs tested, siRNA no. 3 and PELP1 pool showed substantial and consistent reduction in the PELP1 levels, and therefore these two siRNAs were used in the study.
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, and ERß
To understand the significance of PELP1 and ERs, we first surveyed the spatial distribution of PELP1, ER, and ERß immunostaining in the proliferative and secretory phases of the menstrual cycle and in the postmenopausal phase of the human endometrium. The representative pattern is shown in Fig. 1
. Staining intensity and the cellular localization of these proteins in the glandular and stromal compartments in the proliferative and secretory phases and the postmenopausal phases are summarized in Table 1. In the proliferative and secretory phases, PELP1 was expressed in both the glandular and stromal compartments and was localized in both the nucleus and cytoplasm of these cells. Similarly, there were no marked differences in staining between the proliferative and secretory phases (Fig. 1A, top, and Table 1). In contrast, in the postmenopausal sections, PELP1 staining was observed only in the glandular compartment and confined in the cytoplasm of the cells (Fig. 1B, top, and Table 1).
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was observed in the glandular cells of both proliferative and secretory phases. In the stromal cells, however, nuclear staining was prominent in the proliferative phase and decreased drastically in the secretory phase (Fig. 1A
, middle, and Table 1). In the postmenopausal sections, the nuclei stained strong for ER in both the glandular and stromal cells (Fig. 1B, middle, and Table 1). The glandular cells showed prominent cytoplasmic staining for ERß in both the proliferative and secretory phases. In the stromal cells, staining was less prominent in the proliferative phase and increased in the secretory phase (Fig. 1A, lower, and Table 1). However, in the postmenopausal stage, the glandular cells showed strong cytoplasmic staining, and the cells of the stroma showed very weak staining (Fig. 1B, lower). Because both PELP1 and ERß were confined to the cytoplasm of the glandular cells in tissue from postmenopausal women, a time when women are more prone to endometrial cancer, these findings raised the possibility of a relationship between these molecules and tumorigenesis.
PELP1 interacts with ERs and acts as a coactivator of both ER and ERß in endometrial cancer cells
We then analyzed the expression of PELP1 in widely used endometrial cell lines (Ishikawa and RL 95–2) and in control MCF-7 (ER positive) and MDA-MB-231 (ERß positive) breast cancer cells. PELP1 was widely expressed in endometrial cancer cells (Fig. 2A). To examine whether PELP1 positively contributes to E2-mediated signaling in endometrial cells, we performed ER transactivation assays using ER-positive Ishikawa cells as a model system. Coexpression of PELP1 increased ERE-luc activity in ligand-stimulated cells by 9-fold, compared with 6-fold observed in vector-transfected cells, suggesting that PELP1 also acts as a coactivator of ER in endometrial cells (Fig. 2B).
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- or ERß-specific ligands. When PELP1-transfected cells were treated with PPT (29), the ER-specific ligand, 3XERE-luc reporter activity was increased nine times more than the vector-transfected control (Fig. 2C), suggesting that PELP1 coactivates ER-dependent transcription and cooperates with the endogenous ER and its specific ligand PPT. In consonance with these results, treatment of Ishikawa cells with E2 resulted in an enhanced association of PELP1 with ER in vivo (Fig. 2D). As shown in Fig. 2E, treatment of Ishikawa cells with an ERß-specific ligand DPN (29) also stimulated ERE-luc activity, though only three times more than seen in control cells, suggesting that PELP1 can also cooperate with the transcriptional activity of ERß. To validate these results, we showed that PELP1 also promotes ERß transcriptional activity in Ishikawa cells when cotransfected with PELP1 (Fig. 2F). These findings are relevant to the biology of endometrial cancer cells because endogenous PELP1 effectively interacts with ERß in Ishikawa cells in a ligand-dependent manner (Fig. 2G). Collectively these results suggest that PELP1 acts as a coactivator of both ER subtypes; however, PELP1 exhibited more magnitude of coactivation with ER compared with ERß in Ishikawa cells. Status of the PELP1 protein controls the magnitude of ER response
To examine the potential role of PELP1 in ERE-mediated transcription in endometrial cells, we selectively knocked down the endogenous PELP1 expression using the siRNA methodology. The efficacy of PELP1-specific siRNA in down-regulating endogenous PELP1 was confirmed by Western blotting (Fig. 3A), which showed a 70–80% reduction in the level of endogenous PELP1 compared with cells treated with control siRNA. We also found that down-regulation of PELP1 caused a significant decrease in 3XERE-luc reporter gene activity after ligand treatment, compared with cells treated with control siRNA (Fig. 3B). We next examined the effect of PELP1 down-regulation on the growth of E2-stimulated Ishikawa cells. Estrogen stimulated growth of control siRNA-treated Ishikawa cells, whereas down-regulation of PELP1 by siRNA was accompanied by some reduction in the basal proliferation as well as the ability of estrogen to stimulate the growth of Ishikawa cells (Fig. 3C). These results suggest that PELP1 signaling plays an important role in generating optimal E2 responses in endometrial cells.
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Tamoxifen behaves as an agonist in endometrial tissue. It is speculated that the tissue-specific expression of novel regulators or the specific modification of coregulators contributes to the tamoxifen’s agonism (4). Because PELP1 is a novel coactivator, we examined whether PELP1 cooperates with tamoxifen in endometrial cancer cells. We found that the expression of PELP1 substantially increased the tamoxifen-mediated agonist response in the endometrial cell line (Fig. 3D), whereas it had no such effect in MCF-7 cells, in which tamoxifen behaved as an antagonist of the estrogen response (Fig. 3E). Consistent with a potential interaction of PELP1 with tamoxifen-responsive pathways, the interaction of PELP1 with ER increased after treatment with tamoxifen (Fig. 3F). These results suggest that PELP1 has a role in tamoxifen-mediated agonist actions in endometrial cells.
Expression of PELP1 and ERs in endometrial tumors
To understand the physiological significance of PELP1 in endometrial cancer, we next examined the expression of PELP1 in sections of cancerous endometrium. For this, we first determined the levels of PELP1 in five endometrial tumor lysates. The expression of PELP1 was higher in endometrial tumor samples than in the postmenopausal specimens, which showed very weak expression (Fig. 4A). Interestingly, four of five endometrial tumors exhibited weak ER expression compared with ERß, which showed increased expression in all tumors. To gain further insight into the subcellular localization of PELP1 in tumors, we immunostained PELP1 in a subset of 60 endometrial tumors. PELP1 was expressed in all the tumors, but the subcellular localization of PELP1was variable. Specifically, in 31.6% (19 of 60) of the tumor samples, cytoplasmic staining was prominent (Table 2), and an intense nuclear staining was observed in only 6.6% (4 of 60) of tumors (Table 2), whereas both nuclear and cytoplasmic PELP1 staining was observed in 61.6% (37 of 60) of the endometrial tumor specimens. The percentages of tumors showing cytoplasmic, nuclear, or both nuclear and cytoplasmic staining and their staining intensities are summarized in Table 2.
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, and ERß in a series of carefully selected endometrial tumors from patients with grades 1 and 3 disease (n = 9). The expression of nuclear ER was reduced as one went from grade 1 to 3 (Fig. 5). Interestingly, however, the expression of both PELP1 and ERß was maintained in grade 3 tumors, and PELP1 and ERß showed a distinct cytoplasmic localization in grade 1 and 3 tumors.
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Discussion |
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and ERß and that PELP1 interacts with both receptors in a ligand-dependent manner in endometrial cancer cells. Expression of PELP1 in different stages of endometrial development and its functional interactions with both ER subtypes further suggest that it plays an important role in ER signaling in the endometrium. Estradiol regulates cell proliferation in a wide variety of tissues. Several studies demonstrated that coactivators are critical for efficient proliferation induced by E2 (3, 5, 13). Earlier studies also suggested that ER coactivator PELP1 plays an important role in E2-mediated G1-S progression in breast cancer cells (18). PELP1 interacts with cell cycle switch protein pRb and plays a permissive role in E2-mediated cell cycle progression, presumably via its regulatory interactions with pRb pathway (18). In the present study, using siRNAs that specifically target PELP1, we have demonstrated that PELP1 also plays an essential role in E2-mediated cell proliferation of endometrial cells, further supporting a role of PELP1 in E2-mediated cell cycle progression.
Recently, using biochemical methods and confocal microscopy, we have provided evidence that in breast cancer cells, a substantial amount of PELP1 localizes in the nuclear compartment (19). Ligand stimulation promotes PELP1 localization to the ER target gene promoters and colocalizes with active chromatin. PELP1 also interacts with histones, and such functions have a role in ER transactivation functions (19). In this study, we found that PELP1 localizes to the cytoplasm in the postmenopausal endometrium but localizes to the nucleus during the proliferative and secretory phases of the premenopausal endometrium. Further, we have also observed that in postmenopausal endometrium, ERß is also localized in the cytoplasm. In addition, endogenous PELP1 interacts with ERß and plays a mechanistic role in the enhanced ligand sensitivity of ERß in endometrial cancer cells. Collectively, the results from this study suggest that PELP1-mediated genomic and nongenomic signaling plays an important role in proliferative and secretory phases of endometrium, whereas PELP1-mediated nongenomic functions may play a role in postmenopausal endometrium.
ER coregulatory proteins are suspected to play a role in the generally observed tissue-specific effects of tamoxifen (4). Although tamoxifen has been used to treat breast cancer, tamoxifen use has also been associated with endometrial thickening, dysfunctional uterine bleeding, endometrial polyps, endometrial hyperplasia, and uterine sarcoma (30). Our findings suggest that the coregulator PELP1 may play a role in the tamoxifen-mediated partial agonist action seen in the endometrium, because overexpression of PELP1 promoted tamoxifen-mediated partial agonist action in the endometrial cells but not in the breast cells. It is increasingly accepted that deregulation of nongenomic pathways, such as MAPK activation, plays a role in tamoxifen-mediated agonist actions in endometrial cells (31, 32). Because PELP1 stimulates the Src-MAPK pathway (16), it is possible that the noted partial agonist activity of PELP1 in endometrial cells is also influenced by the nongenomic action of PELP1.
In this study, we observed that ER coactivator PELP1 was widely expressed in endometrial cancer cell lines and also in endometrial adenocarcinoma, which constitutes more than 80% of the cases of endometrial cancer. Interestingly, in tumors, PELP1 was localized predominantly to the cytoplasm; and in several cases, ERß was also localized to the cytoplasm. Because PELP1 acts as a coactivator of ERß, presence of ERß and PELP1 in endometrial tumors raises a possibility that ERß-PELP1 signaling may play a role in endometrial tumorigenesis. Because the level of PELP1 is modulated by a ligand-dependent pathway (33), the increased expression seen in endometrial tumors could reflect up-regulation of the E2-ER signaling pathway. It is also possible that the up-regulation of PELP1 helps to hypersensitize ER signaling, thus causing ER signaling to function as an autocrine loop in the ER-positive tumor cells. Future studies are warranted to test the possibility that PELP1 expression is a marker of endometrial tumor progression.
Several studies have shown ERß to be localized to membranes (34), cytoplasm (35), and mitochondria (36), in addition to its nuclear localization, supporting a potential involvement of ERß in nongenomic signaling. Our findings that ERß is present in the cytoplasm of postmenopausal and grade 3 endometrial tumors suggest nongenomic functions for ERß in the development of endometrial cancer. Interestingly, in platelets, which preferentially express ERß isoform, it was shown that ERß activates Src kinase via nongenomic actions, suggesting a possibility that similar activation of nongenomic signaling may occur in the endometrium (37). Because PELP1/MNAR interacts with ERß and activates Src kinase in an E2-dependent manner, the coexpression and localization of both ERß and PELP1 in a subset of endometrial tumors indicate a role for PELP1 and ERß in the pathobiology of endometrial tumors via activation of nongenomic pathways.
In summary, we have characterized the expression and localization of PELP1, a novel ER coregulatory protein, in benign and cancerous endometrium. Our results suggest that PELP1 plays an important role in the transcriptional responses of both ER isoforms in the endometrial cancer cells. Furthermore, the ability of PELP1 to enhance tamoxifen agonist action, the overexpression of PELP1 in endometrial tumors, and its distinct localization in various stages of endometrium suggest that PELP1 plays a role in the biology of benign and cancerous endometrium.
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Footnotes |
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Abbreviations: DCC, Dextran-coated, charcoal-treated fetal calf serum; DPN, diarylpropionitrile; E2, 17ß-estradiol; ER, estrogen receptor; ERE, estrogen response element; luc, luciferase; MNAR, modulator of nongenomic activity of estrogen receptor; PELP1, proline-, glutamic acid-, and leucine-rich protein-1; PPT, propyl-pyrazole-triol; siRNA, short interference RNA; SRC, steroid receptor coactivator.
Received May 13, 2004.
Accepted August 27, 2004.
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with phosphotidylinositol 2-OH kinase. Steroids 67:935–939[CrossRef][Medline]
. J Biol Chem 276:38272–38279 and ERß in proliferation in the rodent mammary gland. Proc Natl Acad Sci USA 101:3739–3746- and ß-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression. Mol Cell Endocrinol 206:13–22[CrossRef][Medline]
(ER), differentially affect ER extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. Mol Endocrinol 17:2013–2027This article has been cited by other articles:
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