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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1573-1577
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Function of Estrogen-Related Receptor {alpha} in Human Endometrial Cancer

Ai Watanabe, Yoshiyuki Kinoshita, Kenichi Hosokawa, Taisuke Mori, Takeshi Yamaguchi and Hideo Honjo

Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kyoto 602-8566, Japan

Address all correspondence and requests for reprints to: Dr. Yoshiyuki Kinoshita, Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: ykino{at}koto.kpu-m.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: The estrogen-related receptor {alpha} (ERR{alpha}) is an orphan member of the nuclear receptor superfamily that is closely related to estrogen receptor {alpha} (ER{alpha}). ERR{alpha} binds an estrogen response element (ERE), directly competes with ER{alpha} for binding ERE, and represses ERE-dependent transcription in MCF-7 cells, ER-positive breast cancer cells.

Objective: We investigated whether ERR{alpha} modulate some ER-dependent activities in endometrial cancer.

Method: We investigated protein and mRNA expression of ERR{alpha} in endometrial cancer using immunohistochemistry and RT-PCR, respectively. After transient transfection using the ERR{alpha} expression vector (pCI-ERR{alpha}) or ERR{alpha}Si, which suppressed the expression of endogenous ERR{alpha}, Ishikawa cells were assayed for ERE-dependent luciferase activity. Cells stably overexpressing ERR{alpha} were generated and compared with estrogen-dependent and -independent cell growth.

Result: ERR{alpha} was detected in human endometrial cancer tissues by immunohistochemistry. An RT-PCR study showed that mRNA of ERR{alpha} was expressed in four endometrial cancer cell lines (Ishikawa, Hec1a, KLE, and SNGII) and 11 human endometrial tissues. Overexpression of ERR{alpha} repressed estrogen-induced ERE-dependent transcriptional activity in Ishikawa cells. After transfection with ERR{alpha}Si1, the expression of endogenous ERR{alpha} decreased to 0.5-fold, and estrogen-induced ERE luciferase activity increased to 1.5-fold. The cells stably overexpressing ERR{alpha} grew up more slowly than control cells in the presence of 10 nM estradiol.

Conclusion: ERR{alpha} is expressed in human endometrial cancer tissues and cell lines and suppresses ERE-dependent transcriptional activity in the presence of estrogen. ERR{alpha} modulates estrogen-induced activity in estrogen-dependent endometrial cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NUCLEAR HORMONE RECEPTORS (NRs) are transcriptional factors. The transcriptional activity of NRs is often regulated by a specific ligand, but several members of the NR superfamily, referred to as orphan receptors, have an unknown natural ligand (1). Estrogen-related receptor {alpha} (ERR{alpha}) was the first orphan receptor found to share significant sequence similarity to estrogen receptor {alpha} (ER{alpha}) (2, 3). ERs activate transcription in a ligand-dependent manner, but ERRs do not bind natural estrogen (2).

Estrogens are well known as a growth factor in hormone-dependent cancer, such as breast cancer and endometrial cancer (4, 5). The biological effect of estrogens is mediated by direct interaction of the ER with DNA at the estrogen response element (ERE). In previous studies ERRs were found to bind to the ERE and modulate the transcription of several genes in the absence of estrogen. Because ERR{alpha} and ER{alpha} share common target genes, ERR{alpha} is also thought to modify the activational effect of estrogens on a number of gene promoters both by direct DNA binding competition (6, 7, 8) and through direct interaction between ER and ERR{alpha} (9). ERR{alpha} competes with ER{alpha} for binding to the ERE and inhibits ERE-dependent transcription in ER-positive MCF-7 cells, suggesting that initiation of ERE-dependent gene expression depends on the ratio of ERR{alpha} to activated ER{alpha} in the cells (8).

ERR{alpha} mRNA is expressed in a variety of cells and tissues. ERR{alpha} mRNA is expressed and ERR{alpha} immunoreactivity is associated with a poor prognosis in breast cancer (10, 11). ERRs play important roles in some types of breast cancer by modulating or substituting for ER-dependent activities. However, the expression of ERR{alpha} in human endometrial cancer tissues has not been investigated, and its function remains unknown. Therefore, in this study we investigated the expression of ERR{alpha} in endometrial cancer cell lines and tissues and the function of ERR{alpha} in ER-positive Ishikawa endometrial cancer cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell cultures

Ishikawa cells, Hec1a cells, KLE cells, and SNG-II cells are all human endometrial cancer cells. KLE cells were purchased from American Type Culture Collection (Manassas, VA), and SNG-II cells were obtained from Health Science Research Resources Bank (Osaka, Japan). MCF-7 cells, a human breast cancer cell line, were a gift from the Cell Resource Center for Biomedical Research (Institute of Development, Aging, and Cancer, Tohoku University, Tohoku, Japan) and were cultured in RPMI 1640 medium. Ishikawa cells were cultured in MEM, Hec1a cells in McCoy’s 5a medium, KLE cells in DMEM/Ham’s F-12, and SNGII cells in Ham’s F-12, respectively.

Plasmid

The ERR{alpha} expression plasmid was constructed by inserting the full-length human ERR{alpha} gene, amplified from pSG5-ERR{alpha} by PCR, into the pCI-neo vector plasmid that has the neomycin-resistance gene (Promega Corp., Madison, WI) at the EcoRI site. The plasmids pSG5-ERR{alpha}, pCI-ER{alpha}, and pGL3(ERE)3-luciferase (ERE-Luc) were provided by Dr. Shiuan Chen (Beckman Research Institute of the City of Hope, Duarte, CA) (12, 13, 14, 15, 16, 17, 18), and pRL-CMV was purchased from Promega Corp.

For the suppression of endogenous ERR{alpha}, we prepared three kinds of small interfering RNA expression plasmid, ERR{alpha}Si1, ERR{alpha}Si2, and ERR{alpha}Si3; piGENE vector plasmid (iGENE, Therapeutics, Inc., Ibaraki, Japan) was used as a control. The pcRURU6 I cassette vector (iGENE) was used for interfering endogenous ERR{alpha} according to the manufacturer’s protocol (Takarabio, Inc., Kyoto, Japan). The pcRURU6 i cassette vector contains a human U6 promoter, a puromycin resistance gene, and two BspMI sites, which are used as sites for cloning a short hairpin sequence. The target sequences of ERR{alpha}Si1, ERR{alpha}Si2, and ERR{alpha}Si3 were 5'-GGAGTATGTTCTACTAAAG-3', 5'-AGAGGAGTATGTTCTACTA-3', and 5'-GCAGAAACCTATCTCAGGG-3', respectively.

Tissues and immunohistochemistry

Nine specimens of endometrial cancer tissue were obtained from 1999–2003 at Kyoto Prefectural University of Medicine Hospital (Kyoto, Japan). Nine cancer patients (mean age, 62 yr; range, 52–75) did not receive chemotherapy or radiation therapy before surgery. Informed consent was obtained from all patients. All specimens were fixed with 10% formalin and embedded in paraffin wax.

Mouse monoclonal antibody for ERR{alpha} was purchased from Perseus Proteomics, Inc. (Tokyo, Japan); the dilution was 1:125 (11). The EnVision+ kit (DakoCytomation, Copenhagen, Denmark) was used for immunohistochemical analysis. The antigen-antibody complex was visualized with 3,3'-diaminobenzidine solution and counterstained with hematoxylin. According to a previous report (11), the ERR{alpha} labeling index was determined, and values above 10% were considered ERR{alpha} positive.

RT-PCR analysis

All endometrial cancer samples were collected after surgery in 2003 or 2004 at Kyoto Prefectural University of Medicine Hospital. Eleven patients (mean age, 53.3 yr; range 33–74) did not receive any therapy before surgery. Informed consent was obtained from all patients.

Total mRNA were isolated from five cell lines and 11 tissue specimens by the acid guanidinium phenol chloroform method using Sepasol-RNA I (Nacalai Tesque, Inc., Kyoto, Japan). RT-PCR was performed using ReverTra Ace and rTaq DNA polymerase (Toyobo Co. Ltd., Osaka, Japan). The sequences of the oligonucleotide primers and the amplicon sizes were as follows: ER{alpha} forward primer, 5'-GCCAAGGAGACTCGCTACTGT-3'; and reverse primer, 5'-TCCAGAGACTTCAGGGTGCT-3' (875-bp amplicon); ERR{alpha} forward primer, 5'-TGGTCCAGCTCCCACTCGCT-3'; and reverse primer, 5-'TGAGACACCAGTGCATTCACTG-3' (483-bp amplicon); and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) forward primer, 5'-TGAAGGTCGGAGTCAACGGATTTGGT-3'; and reverse primer, 5'-CATGTGGGCCATGAGGTCCACCAC-3' (983-bp amplicon). G3PDH was used as an internal PCR control.

Transient transfection and luciferase assay

Before transfection, cells were cultured in phenol red-free RPMI 1640 with 2.5% dextran-coated charcoal-treated FBS for more than 48 h. Transient transfections were performed in 24-well plates using Lipofectamine reagent (Invitrogen Life Technologies, Inc., Carlsbad, CA). After 6 h of transfection, the medium was replaced with fresh medium containing dimethylsulfoxide (DMSO) or 10 nM estradiol (E2). After 36 h, the cells were lysed, and the lysates were assayed for luciferase activity with the Dual-Glo Luciferase Assay System (Promega Corp.). When it was necessary to suppress endogenous ERR{alpha}, 5% TCX (Celox Laboratories, Inc., St. Paul, MN), a serum replacement, was used.

Generation of Ishikawa stably expressing ERR{alpha} and cell growth assay

Ishikawa cells were transfected with pCI-neo (control) or pCI-ERR{alpha}. A transfected cell was cloned, and individual colonies were picked up and numbered. Semiquantitative RT-PCR analysis of ERR{alpha} was performed, and the signal intensities of the PCR products were quantified by a gel documentation program, Scion Image (Scion Co., Frederick, MD). The most ERR{alpha}-expressing colony clone was cultured for 3 months in the presence of 600 µg/ml G418 (neomycin; Nacalai Tesque). Cells (5 x 103) were placed in each plate, cultured in the presence or absence of 10 nM E2, trypsinized, and counted with a hemocytometer.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Immunoreactivity for ERR{alpha} was strongly detected in two thirds of cancer tissue specimens (Fig. 1AGo).


Figure 1
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  		FIG. 1. A, Immunohistochemical staining for ERR{alpha} in endometrial cancer specimens. ERR{alpha} was strongly detected in endometrial cancer, grade 1. In all photomicrographs, magnification, x400. B and C, Expression of mRNA in endometrial tissues and cell lines. B, Expression of ER{alpha} and ERR{alpha} mRNA in human endometrial cancer tissues. Total RNA was extracted from 11 endometrial cancer tissue specimens and subjected to RT-PCR analysis. C, Expression of ER{alpha} and ERR{alpha} in endometrial cancer cell lines. Total RNA was extracted from endometrial cancer cell lines and subjected to RT-PCR analysis. As a positive control, the breast cancer cell line MCF-7 was used. The PCR conditions were as follows: ER{alpha}, 33 cycles of 94 C for 1 min (denaturation), at 58 C for 1 min (annealing), and at 72 C for 1 min (extension); ERR{alpha}, 35 cycles of 94 C for 1 min, 58 C for 1 min, and 72 C for 1 min; and G3PDH, 33 cycles of 94 C for 1 min, 55 C for 1 min, and 72 C for 1 min. The PCR products were resolved by electrophoresis on 1.2% agarose gel containing ethidium bromide. D, ERR{alpha} suppresses estrogen response in Ishikawa cells. Ishikawa cells were transfected in parallel with 0.0625 µg ERE-luciferase, 0.025 µg pRL-cytomegalovirus, and 0.25 µg pCI-ERR{alpha} or the empty vector pCI-neo. The transfected cells were incubated with DMSO or 10 nM E2 for 36 h. After cells had been washed twice with PBS, they were assayed for luciferase activity as described in Materials and Methods. Results are given as the mean ± SE of data obtained from three separate experiments.

 
At the mRNA level, ERR{alpha} was expressed in all endometrial cancer tissue specimens, and ER{alpha} mRNA was expressed in 10 of the 11 endometrial cancer tissue specimens (Fig. 1BGo). Figure 1CGo shows that ERR{alpha} mRNA was detected in all human endometrial cancer cell lines, and both ER{alpha} mRNA and ERR{alpha} mRNA were expressed in Ishikawa cells.

In the ERR{alpha} transiently overexpression experiment, E2 increased ERE-dependent activity by 7-fold compared with DMSO treatment in cells transfected with PCI-neo vector. In contrast, E2 increased this ERE-dependent activity by only 3-fold in the cells transfected with ERR{alpha} (Fig. 1DGo). It is suggested that ERR{alpha} repressed estrogen-induced transcriptional activity in ER-positive Ishikawa cells.

ERR{alpha}Si1 decreased the levels of endogenous ERR{alpha} to half compared with controls (Fig. 2AGo). After transfection with ERR{alpha}Si1, ERE-dependent transcriptional activity was decreased in the absence of E2 and serum. In contrast, E2-induced ERE reactivity was increased to 1.5-fold (Fig. 2BGo). Suppressing endogenous ERR{alpha} decreased E2-independent, ERE-dependent transcriptional activity, but enhanced E2-induced, ERE-dependent transcriptional activity. ERR{alpha} clone 4 cells stably overexpressing ERR{alpha} expressed ERR{alpha} mRNA at levels 1.5-fold higher than control (neo) values (Fig. 2CGo). Ishikawa ERR{alpha} clone 4 cells grew more slowly than control (neo) cells in the presence of E2 (Fig. 2DGo).


Figure 2
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  		FIG. 2. A, Suppression of ERR{alpha} by ERR{alpha}Si in Ishikawa cells. Ishikawa cells were transfected with three kinds of pcRURU6i-ERR{alpha}Si (ERR{alpha}Si1, ERR{alpha}Si2, and ERR{alpha}Si3), which express small interfering RNA for ERR{alpha}, or with piGENE as a control and cultured for 48 h. Total RNA was extracted and subjected to RT-PCR analysis. The expression intensities of endogenous ERR{alpha} were normalized to those of G3PDH and compared. Results are given as the mean ± SE of data obtained from three separate experiments. B, ERR{alpha}Si1 enhanced E2-induced ERE promoter activity in Ishikawa cells. Ishikawa cells were transfected in parallel with 0.05 µg ERE-luciferase, 0.02 µg cytomegalovirus-luciferase, and 0.4 µg ERR{alpha}Si1 or the empty vector, piGENE. The transfected cells were cultured for 36 h in medium containing TCX with DMSO ({blacksquare}) or 10 nM E2 ({square}). The ratio shows the estrogen reactivity [luciferase activity (E2)/luciferase activity (DMSO)]. After cells had been washed twice with PBS, they were assayed for luciferase activity as described in Materials and Methods. Results are given as the mean ± SE of data obtained from three separate experiments. C, Expression of ERR{alpha} mRNA in Ishikawa cells stably overexpressing ERR{alpha}. Ishikawa cells (50 x 104) were placed in six-well plates and transfected in parallel with 2.5 µg pCI-neo (neo) or pCI-ERR{alpha}(ERR{alpha}). Before selection with 600 µg/ml G418, the culture was incubated for 48 h. Semiquantitative RT-PCR analysis of ERR{alpha} was performed on the colony cells picked up (no. 1–4). ERR{alpha} clone 4 cells that expressed ERR{alpha} mRNA at levels 1.5-fold higher than controls (neo) were subcultured in 75-cm2 flasks for 3 months in medium containing G418. Results are given as the mean ± SE of data obtained from three separate experiments. D, Effect of ERR{alpha} on cell growth in the presence or absence of estrogen. Five thousand cells per well (neo, ERR{alpha}) were cultured in six wells in the presence or absence of 10 nM E2. The medium was changed on d 1, 3, and 6, and the cells were counted on d 3, 6, and 9. Results are given as the mean ± SE of data obtained from three separate experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study we showed that ERR{alpha} is expressed in endometrial cancer tissue at both mRNA and protein levels. Immunoreactivity for ERR{alpha} was detected in two thirds of cancer tissue specimens, and ERR{alpha} mRNA was detected in all endometrial cancer tissue specimens and cell lines. The expression of ERR{alpha} was very high in endometrial cancer. Suzuki et al. (11) detected ERR{alpha} immunoreactivity in 55% of breast cancers and found that it was associated with ERR{alpha} mRNA levels and positively associated with ER{alpha} status. It was suggested that the expression of ERR{alpha} in endometrial cancers is higher than that in breast cancers. Although a higher level of ER leads to a better prognosis and treatment of breast cancer, ERR{alpha} was associated with a poor prognosis. In our study there is no association between the expression of ERR{alpha} and that of ER{alpha}, but the relationships among these factors and the association with prognosis in endometrial cancer are not clear.

ERRs bind to the ERE and modulate the transcription of at least several genes, such as pS2 (10), aromatase (12, 13, 14), and lactoferrin (9, 19), in the absence of estrogen, but ERR{alpha} activity depends on a serum compound that is removed by charcoal treatment, which, according to previous report (20), suggests the existence of a regulating factor present in serum. In this study to identify the function of endogenous ERR{alpha} in endometrial cancer cells, we used a serum replacement for the suppressing study. Transient transfection with ERR{alpha}Si1 suppressed the expression of endogenous ERR{alpha} in Ishikawa cells and decreased ERE-dependent transcriptional activity in the absence of estrogen. This implies that endogenous ERR{alpha} had already activated ERE in the absence of serum and estrogen. Furthermore, estrogen-induced ERE luciferase activity was increased by the suppression of endogenous ERR{alpha}. In addition, the overexpression of ERR{alpha} repressed estrogen-induced, ERE-dependent transcriptional activity. It was also reported that both ER{alpha} and ERR{alpha} directly compete for binding to EREs and down-modulate the transcriptional response to estrogen in an ERE-dependent manner (7, 8). Our data support the hypothesis that endogenous ERR{alpha} suppresses ER-dependent estrogen-induced, ERE-dependent transcriptional activity in endometrial cancer as well as breast cancer. Using an ERR{alpha} expression plasmid, we found that cells stably overexpressing ERR{alpha} grew more slowly than control cells in the presence of estrogen. ERR{alpha}, therefore, functions as a repressor of the ER{alpha}-dependent promoter in ER{alpha}-positive cells in the presence of estrogen. ERR{alpha} operates as an activator or repressor of ERE-dependent transcription based upon other properties of the cell.

In summary, we have shown that ERR{alpha} is expressed in endometrial cancers, and that the transcriptional function of ERR{alpha} involves binding to an ERE. ERR{alpha} immunoreactivity was detected in many endometrial cancer tissue specimens, but it is not clear whether the expression of ERR{alpha} is associated with endometrial carcinogenesis, because data from normal endometrium were not investigated. ERR{alpha} down-modulated estrogen-induced, ERE-dependent transcriptional activity in ER-positive endometrial cancer cells, and the cells stably overexpressing ERR{alpha} grew more slowly than control cells in the presence of estrogen. It is suggested that ERR{alpha} regulated cell growth differently in the absence and presence of estrogen in endometrial cancer.


   Footnotes
 
All authors have nothing to declare.

First Published Online February 7, 2006

Abbreviations: DMSO, Dimethylsulfoxide; E2, estradiol; ER, estrogen receptor; ERE, estrogen response element; ERR{alpha}, estrogen-related receptor {alpha}; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; NR, nuclear hormone receptor.

Received September 6, 2005.

Accepted January 27, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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