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Endocrinology |
in Human Breast Carcinoma as a Potent Prognostic Factor
Departments of 1 Pathology and 2 Surgery, Tohoku University School of Medicine, Sendai, Japan; and 3 Department of Surgery, Tohoku Kosai Hospital, Sendai, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(ERR) was identified as a gene related to estrogen receptor (ER) and belongs to a class of nuclear orphan receptors. ERR binds to estrogen responsive element(s) (ERE) and is considered to be involved in modulation of estrogenic actions. However, biological significance of ERR remains largely unknown. Therefore, we examined the expression of ERR in human breast carcinoma tissues using immunohistochemistry (n = 102) and real-time reverse transcription-PCR (n = 30). ERR immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancers examined, and relative immunoreactivity of ERR was significantly (P = 0.0041) associated with the mRNA level. Significant associations were detected between ER and ERE-containing estrogen-responsive genes, such as pS2 (P < 0.0001) and EBAG9/RCAS1 (P = 0.0214), in breast carcinoma tissues. However, no significant association was detected between ER and pS2 (P = 0.1415) in the ERR-positive cases (n = 56) or between ER and EBAG9/RCAS1 (P = 0.8271) in the ERR-negative group (n = 46). ERR immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- (P = 0.0097 and P = 0.0053, respectively) and multi- (P = 0.0215 and P = 0.0118, respectively) variate analyses. A similar tendency was also detected in the group of breast cancer patients who received tamoxifen therapy after surgery. Results from our study suggest that ERR possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERR immunoreactivity is a potent prognostic factor in human breast carcinoma. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and/or ß (3)
. ERs activate transcription of various target genes (i.e., estrogen responsive genes) in a ligand-dependent manner by direct DNA interaction through the estrogen-responsive element(s) (ERE) or by tethering to other transcription factors (4
, 5)
. Therefore, antiestrogens such as tamoxifen, which blocks ER, have been mainly used as an endocrine therapy in breast carcinoma for many years.
Estrogen-related receptor (ERR) family belongs to nuclear hormone receptors, and consists of three closely related members (, ß, and 
; Refs. 6
and 7
). ERRs share significant homology to ER at the DNA-binding domain and recognize the ERE (8, 9, 10)
, which indicates that ERRs modulate the actions of ERs (11, 12, 13)
. However, ERRs are not activated by known natural estrogens and are therefore classified as orphan receptors (14)
. ERRs can also bind to steroidgenic factor 1 (SF1)-binding element within the promoter regions of various steroidogenic P450 genes including aromatase (15
, 16)
.
Previous in vitro studies have demonstrated the mRNA expression of ERR in breast cancer cell lines (17)
and breast carcinoma tissues (18)
. ERR activated the expression of pS2, one of the estrogen responsive genes (17)
, in breast cancer cells, and it has also been reported that ERR regulated aromatase expression in breast fibroblasts (11)
. However, a detailed examination of ERR expression, including at the protein level, has not been examined in human breast carcinoma tissues, and the biological significance of ERR remains largely unclear. Therefore, in this study, we examined the immunolocalization of ERR in 102 cases of human breast carcinoma tissues and correlated these findings with various clinicopathological factors including the clinical outcome. In addition, we also examined mRNA expression of ERR in 30 cases of breast carcinoma tissues using real-time reverse transcription-PCR and analyzed the correlation with the ERR immunoreactivity or aromatase mRNA expression.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Thirty specimens of invasive ductal carcinoma were obtained from patients who underwent mastectomy in 2000 in the Departments of Surgery at Tohoku University Hospital and Tohoku Kosai Hospital, Sendai, Japan. Specimens of adipose tissue adjacent to the carcinoma and non-neoplastic breast tissues were available for examination in 7 and 5 of these 30 cases, respectively. Specimens for RNA isolation were snap-frozen and stored at –80°C, and those for immunohistochemistry were fixed with 10% formalin and embedded in paraffin-wax. Informed consent was obtained from all patients before their surgery and examination of specimens used in this study.
Research protocols for this study were approved by the Ethics Committee at both Tohoku University School of Medicine and Tohoku Kosai Hospital.
Antibodies.
Mouse monoclonal antibody for ERR (2ZH5844H) was purchased from Perseus Proteomics Inc. (Tokyo, Japan). This antibody was produced by immunizing mice with a systemic peptide corresponding to amino acids 98–171 of ERR (GenBank accession number; X51416), and the characterization was confirmed by immunoblotting analyses.4
Rabbit polyclonal antibody for estrogen sulfotransferase (EST; SULT 1E1 gene; PV-P2237; Ref. 20
) was purchased from Medical Biological Laboratory (Nagoya, Japan). EBAG9/RCAS1 antibody was a rabbit polyclonal antibody (21
, 22)
and was kindly provided from Dr. S. Inoue (Department of Biochemistry, Saitama Medical School, Saitama, Japan). Monoclonal antibodies for ER (ER1D5), progesterone receptor (PR; MAB429), Ki-67 (MIB1), pS2 (M7184), cyclin D1 (P2D11F11), and c-myc (1–6E10) were purchased from Immunotech (Marseille, France), Chemicon (Temecula, CA), DAKO (Carpinteria, CA), DAKO, Novocastra Laboratories (Newcastle, United Kingdom), and Cambridge Research Biochemical (Cambridge, United Kingdom), respectively. Rabbit polyclonal antibodies for ERß (06–629) and human epidermal growth factor receptor 2 (HER2; A0485) were obtained from Upstate Biotechnology (Lake Placid, NY) and DAKO, respectively.
Immunohistochemistry.
A Histofine kit (Nichirei, Tokyo, Japan), which uses the streptavidin-biotin amplification method, was used for the identification of ERR, ER, PR, EST, HER2, Ki-67, pS2, EBAG9/RCAS1, cyclin D1, and c-myc immunoreactivity, whereas EnVision+ (DAKO) was used for ERß immunohistochemical analysis. Antigen retrieval for ERR, ER, ERß, PR, HER2, Ki-67, EBAG9/RCAS1, and cyclin D1 immunostaining was performed by heating the slides in an autoclave at 120°C for 5 min in citric acid buffer [2 mM citric acid and 9 mM trisodium citrate dehydrate (pH 6.0)], and similarly, antigen retrieval for EST and pS2 immunostaining was done by heating the slides in a microwave oven for 15 min in a citric acid buffer. Dilutions of primary antibodies used in this study were as follows: ERR, 1:1000; ER, 1:50; ERß, 1:50; PR, 1:30; EST, 1:9000; HER2, 1:200, Ki-67, 1:50; pS2, 1:30; EBAG9/RCAS1, 1:20; cyclin D1, 1:40; and c-myc 1:600. The antigen-antibody complex was visualized with 3,3'-diaminobenzidine solution (1 mM 3,3'-diaminobenzidine, 50 mM Tris-HCl buffer (pH 7.6), and 0.006% H2O2) and counterstained with hematoxylin.
Human tissues of heart were used as positive controls for ERR immunohistochemistry (23)
. As a negative control for ERR immunohistochemistry, normal mouse IgG was used instead of the primary antibody for ERR, and no specific immunoreactivity was detected in these sections.
Real-Time Reverse Transcription-PCR.
Total RNA was carefully extracted with guanidinium thiocyanate followed by ultracentrifugation in cesium chloride. A reverse transcription kit (SUPERSCRIPT II Preamplification system; Life Technologies, Inc., Grand Island, NY) was used in the synthesis of cDNA.
The Light Cycler System (Roche Diagnositics GmbH, Mannheim, Germany) was used to semi-quantify the mRNA level of ERR, aromatase, and ribosomal protein L 13a (RPL13A) by real-time reverse transcription-PCR (24)
. Settings for the PCR thermal profile were as follos: initial denaturation at 95°C for 1 min followed by 40 amplification cycles of 95°C for 1 s, annealing at 62°C (ERR), 60°C (aromatase), or 68°C (RPL13A) for 15 s, and elongation at 72°C for 15 s. The primer sequences used in this study are as follows: ERR [X51416; forward 5'-TGCTCAAGGAGGGAGTGC-3' (cDNA position; 785–802) and reverse 5'-GGCGACAATTTCTGGTTCGGGTCAGGCATGGCATAG-3' (cDNA position; 981–998)], aromatase [(X13589; Ref. 20
; forward 5'-GTGAAAAAGGGGACAAACAT-3' (cDNA position; 1286–1305) and reverse 5'-TGGAATCGTCTCAGAAGTGT-3' (cDNA position; 1481–1500)], and RPL13A [(NM012423; 25
; forward 5'-CCTGGAGGAGAAGAGGAAAGAGA-3' (cDNA position; 487–509) and reverse 5'-TTGAGGACCTCTGTGTATTTGTCAA-3' (cDNA position; 588–612)]. Oligonucleotide primers for ERR were designed in different exons to avoid the amplification of genomic DNA or human ERR pseudo-gene (U85258). To verify amplification of the correct sequences, PCR products were purified and subjected to direct sequencing. Human heart tissue was used as a positive control for ERR, whereas human placental tissue was used as a positive control for aromatase. Negative control experiments lacked cDNA substrate to check for the possibility of exogenous contaminant DNA, and no amplified products were detected under these conditions. mRNA level for ERR and aromatase in each case has been summarized as a ratio of RPL13A and subsequently evaluated as a ratio (%) compared with that of the positive controls.
Scoring of Immunoreactivity and Statistical Analysis.
ERR, ER, ERß, PR, and Ki-67 immunoreactivity was scored in >1000 carcinoma cells for each case, and the percentage of immunoreactivity, i.e., labeling index (LI), was determined. In this study, cases that were found to have ERR LI of >10% were considered ERR-positive breast carcinomas, according to a report for ER and PR by Allred et al. (26)
. Immunoreactivity of EST was classified into the following three categories: ++, >50% positive cells; +, 1–50% positive cells; and –, no immunoreactivity, according to a previous report (20)
.
Values for LIs for ERR, ER, ERß, PR, Ki-67, ERR mRNA level, patient age, and tumor size were summarized as a mean ± 95% confidence interval. The association between immunoreactivity for ERR status and these parameters were evaluated using a one-way ANOVA and Bonferroni test. The association between ERR and PR LIs, and the association between ERR mRNA and ERR LI or aromatase mRNA were performed using a correlation coefficient (r) and regression equation. Statistical difference between ERR status and menopausal status, stage, lymph node status, histological grade, ER status, EST, or HER2 status was evaluated in a cross-table using the 
2 test. Overall and disease-free survival curves were generated according to the Kaplan-Meier method, and the statistical significance was calculated using the log-rank test. Univariate and multivariate analyses were evaluated by Cox proportional hazards model using PROC PHREG in our SAS software. Differences with Ps < 0.05 were considered significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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in Breast Carcinoma Tissues. was detected in the nuclei of invasive ductal carcinoma cells (Fig. 1A)
. A mean value of ERR LI in the 102 breast carcinoma tissues examined was 23.0% (range 0–75%), and a number of ERR-positive breast carcinomas (i.e., ERR LI 
10%) was 56 of102 cases (54.9%). ERR immunoreactivity was focally detected in epithelial cells of morphologically normal glands (Fig. 1B)
, whereas the stroma or adipose tissue was immunohistochemically negative for ERR. A mean value of ERR LI in non-neoplastic mammary epithelia was 14.6% (range 0–33%), and the number of cases showing higher ERR LI in carcinoma cells than that in non-neoplastic mammary epithelia was 49 of 102 (48.0%). In positive control sections for ERR immunohistochemistry, ERR immunoreactivity was markedly detected in the nuclei of myocardial cells of the heart (Fig. 1C)
.
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immunoreactivity and clinicopathological parameters in 102 breast carcinomas are summarized in Table 1
. ERR immunoreactivity tended to be positively associated with ER status and ER LI and negatively associated with EST; however the correlation did not reach a statistical significance (P = 0.0848, P = 0.1485, and P = 0.1224, respectively). No significant association was detected between ERR immunoreactivity and the other clinicopathological parameters examined, including patient age, menopausal status, stage, tumor size, lymph node status, histological grade, ERß LI, PR LI, HER2 status, and Ki-67 LI, in this study.
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Status on the Association between ER and Estrogen Responsive Genes.
, a significant positive association was detected between ER LI and the status of these immunoreactivity genes except for c-myc in the 102 breast cancer tissues examined (P < 0.0001 for pS2, P = 0.0214 for EBAG9/RCAS1, P < 0.0001 for PR LI, P = 0.0002 for cyclin D1, and P = 0.9372 for c-myc), which agrees well with previous immunohistochemical studies (22
, 27, 28, 29, 30)
. However, when the breast cancers were classified into two groups according to ERR status, no significant association was detected between ER LI and pS2 in the group of ERR-positive breast carcinomas (P = 0.1415; n = 56) or between ER LI and EBAG9/RCAS1 in ERR-negative breast cancers (P = 0.8271; n = 46). On the other hand, significant association was detected between ER LI and PR LI (P < 0.0001 in ERR-positive cases; P < 0.0001 in ERR-negative cases) or cyclin D1 (P = 0.0126 in ERR-positive cases; P = 0.0082 in ERR-negative cases), regardless of the ERR status in the breast cancer cases examined.
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LI and these estrogen-responsive genes regardless of ER status in 102 breast carcinoma tissues (Table 3)
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Immunoreactivity and the Clinical Outcome of the Patients. immunoreactivity was significantly associated with an increased risk of recurrence (P = 0.0071, log-rank test; Fig. 2A
). After univariate analysis by Cox proportional hazards model (Table 4)
, lymph node status (P < 0.0001), tumor size (P < 0.0001), EST (P = 0.0035), and ERR immunoreactivity (P = 0.0097) were demonstrated as significant prognostic parameters for disease-free survival in 102 breast carcinoma patients. A multivariate analysis (Table 4)
, however, revealed that only lymph node status (P = 0.0015) and ERR immunoreactivity (P = 0.0215) were independent-prognostic factors with relative risks over 1.0, whereas tumor size and EST were not significant.
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, and a significant correlation was detected between ERR immunoreactivity and adverse clinical outcome of the patients (P = 0.0018, log-rank test). Using a univariate analysis (Table 5)
, lymph node status (P < 0.0001), tumor size (P = 0.0002), ERR immunoreactivity (P = 0.0053), EST (P = 0.0065), HER2 status (P = 0.0175), adjuvant chemotherapy (P = 0.0233), and histological grade (P = 0.0310) turned out to be significant prognostic factors for overall survival in this study. Multivariate analysis revealed that lymph node status (P = 0.0085), ERR immunoreactivity (P = 0.0118), and EST (P = 0.0382) were independent-prognostic factors with a relative risk over 1.0; however other factors were not significant in this study (Table 5)
.
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-positive breast cancers. The disease-free and overall survival curves in these patients were summarized in Fig. 2, C and D
. ERR immunoreactivity was also markedly associated with an increased risk of recurrence and worse prognosis in the group of breast cancer patients who received tamoxifen therapy, although Ps were not available because no patient had a recurrence or died in the group of ERR-negative breast cancers. Association between ERR immunoreactivity and clinical outcome of the patients was not significantly changed regardless of the status of adjuvant chemotherapy after surgery in this study (data not shown).
ERR mRNA Expression in the Breast Carcinoma Tissues.
mRNA expression for ERR, aromatase, and RPL13A was detected as a specific single band (214, 215, and 126 bp, respectively) and was semi-quantified by real-time reverse transcription-PCR. Expression of ERR mRNA was detected markedly in the breast carcinoma tissues (65.7 ± 9.0%) but was low in non-neoplastic breast tissues (25.4 ± 6.0%, P = 0.0448 versus carcinoma tissues) or adipose tissues adjacent to the carcinoma (12.6 ± 7.3%, P = 0.0174 versus carcinoma tissues; Fig. 3A
). ERR mRNA expression was closely correlated with the ERR immunoreactivity evaluated as ERR LI (P = 0.0041, r = 0.509) in 30 breast carcinoma tissues examined (Fig. 3B)
. However, mRNA expression of ERR was not significantly associated with that of aromatase (P = 0.6441, r = -0.088) in this study (Fig. 3C)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancer tissues and was significantly associated with its mRNA level. ERR mRNA expression was demonstrated previously in various human breast cancer cell lines, breast carcinoma tissues, and normal mammary epithelial cells (17
, 18) , and our present findings were in good agreement with these previous reports. Results in our present study also demonstrated that ERR immunoreactivity tended to be positively or inversely associated with ER or EST, respectively. The possible correlation between ERR and ER expression remains controversial. Ariazi et al. (18)
reported that increased ERR mRNA levels were associated with ER-negative and PR-negative tumor status in 38 breast cancer tissues and suggested a possible unfavorable marker in the breast cancers. However, Liu et al. (31)
demonstrated that estrogens stimulate the expression of ERR in the human breast cell lines, and suggested that ERR is a downstream target of ER. On the other hand, EST catalyzes estrogens to biologically inactive estrogen sulfates (32
, 33)
and is considered to diminish estrogen actions in the breast cancers (20)
. Therefore, our present results suggest that expression of ERR is, at least in a part, associated with estrogenic actions.
In our present study, significant associations were detected between ER and estrogen responsive genes such as pS2, EBAG9/RCAS1, PR, and cyclin D1, as was reported previously (22
, 27, 28, 29)
. However, the significant association between ER and pS2 or EBAG9/RCAS1 disappeared in the group of ERR-positive or -negative breast cancers, respectively. On the other hand, correlation between ER and PR, cyclin D1, or c-myc was not influenced by ERR status in these breast cancer patients examined. Both pS2 and EBAG9/RCAS1 genes are induced by ER through an ERE in the promoter region (34
, 35)
. However, functional ERE has not been identified in PR (36)
and cyclin D1 (5)
, and these are considered to be induced by ER through the interaction between ER and other DNA-binding transcription factors. Considering that ER and ERR directly compete for binding EREs (13)
, our present data suggest that ERR mainly modulates ER-mediated ERE-dependent transcription and changes the expression pattern of estrogen-responsive genes in the breast cancer cells.
ERR immunoreactivity was significantly associated with an increased risk of recurrence or adverse clinical outcome of the patients, and results of multivariate analyses demonstrated that ERR immunoreactivity is an independent-prognostic factor. Estrogens induce various estrogen responsive genes in breast cancer cells, and these genes include not only activators of cell growth such as cyclin D1 (37)
or c-myc (38)
but also relatively good prognostic markers such as pS2 (29)
or PR (39)
. ERRs display significant constitutive transcriptional activity (7
, 9
, 40)
. Therefore, poor clinical outcome in ERR-positive breast cancer patients may be partly caused by constitutive modulation of the expression of estrogen-responsive genes, although we could not directly demonstrate such hypothesis from our present data, because of the lack of mechanistic examinations and the relatively limited number of cases examined in this study. Additional examinations are required to clarify the detailed mechanism of ERR action in the breast cancer tissues.
ERR immunoreactivity was also associated with poor prognosis in the group of breast cancer patients who received tamoxifen therapy, which suggests that ERR status is a possible predictive marker for tamoxifen therapy, although the number of cases examined was limited in this study. Previous in vitro studies demonstrated that both tamoxifen and 4-hydroxytamoxifen did not bind to ERR or did not have any effects on the transcriptional activity of ERR, whereas these are high-affinity ligands for ERRß or ERR (41
, 42)
. Therefore, ERR may constitutively function independently of tamoxifen and result in tamoxifen resistance in ERR-positive breast cancer patients.
Aromatase is a key enzyme in in situ estrogen biosynthesis in breast cancer tissue, and aromatase inhibitors are currently used in breast cancer patients as an endocrine therapy as well as antiestrogens. Aromatase is markedly activated by SF1 through an SF1-binding element within the promoter region (43)
. However, SF1 is not expressed in breast carcinoma tissues (11
, 44)
. Previously, Yang et al. (11)
reported the induction of aromatase expression by ERR through a SF1-binding element in breast fibroblast, suggesting the possible importance of ERR as a regulator of aromatase expression in breast cancer. However, in our study, we did not find ERR immunoreactivity in the intra-tumoral stromal cells or adipocytes adjacent to the carcinoma, although these cells are well-known to express aromatase (45)
. Previous in vitro studies have shown the regulation of aromatase transcription in breast fibroblasts and/or adipocytes by various factors, including cytokines (46)
, prostaglandin E2 (47)
, liver receptor homologue-1 (44)
and CCAAT/enhancer-binding protein ß (48)
.
In summary, ERR immunoreactivity was detected in carcinoma cells in 55% of breast cancer tissues and was associated with its mRNA level. Association between ER and ERE-containing estrogen-responsive genes was markedly altered according to ERR status in the breast cancer tissues. ERR immunoreactivity was associated with poor prognosis of the patients, and similar tendency was also detected in the group who received tamoxifen therapy. These findings suggest that ERR possibly modulates the expression of ERE-containing estrogen responsive genes, and ERR immunoreactivity is a potent prognostic factor, including a possible predictive marker for tamoxifen resistance, in human breast carcinoma.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Requests for reprints: Takashi Suzuki, Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. Phone: 81-22-717-8050; Fax: 81-22-717-8051; E-mail: t-suzuki{at}patholo2.med.tohoku.ac.jp
4 Perseus Proteomics Inc., unpublished data. 
Received 1/26/04. Revised 4/ 1/04. Accepted 5/ 4/04.
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J. Zhou, T. Suzuki, A. Kovacic, R. Saito, Y. Miki, T. Ishida, T. Moriya, E. R. Simpson, H. Sasano, and C. D. Clyne Interactions between Prostaglandin E2, Liver Receptor Homologue-1, and Aromatase in Breast Cancer Cancer Res., January 15, 2005; 65(2): 657 - 663. [Abstract] [Full Text] [PDF]
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D. P. McDonnell The Molecular Pharmacology of Estrogen Receptor Modulators: Implications for the Treatment of Breast Cancer Clin. Cancer Res., January 15, 2005; 11(2): 871s - 877s. [Abstract] [Full Text] [PDF]
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J. C. Carrier, G. Deblois, C. Champigny, E. Levy, and V. Giguere Estrogen-related Receptor {alpha} (ERR{alpha}) Is a Transcriptional Regulator of Apolipoprotein A-IV and Controls Lipid Handling in the Intestine J. Biol. Chem., December 10, 2004; 279(50): 52052 - 52058. [Abstract] [Full Text] [PDF]
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