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Expression Analysis of Estrogen Receptor Coregulators in Breast Carcinoma

Evidence That NCOR1 Expression Is Predictive of the Response to Tamoxifen¹

Laboratoire d’Oncogénétique, Institut National de la Santé et de la Recherche Médicale E0017 [I. G., F. L., S. T., R. L., I. B.] and Département de Médecine [M. T-H.], Centre René Huguenin, F-92211 St-Cloud, and Laboratoire de Génétique Moléculaire, Unité Propre de Recherche et d’Enseignement Supérieur JE 2195, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris V, F-75006 Paris [I. B.], France

	ABSTRACT

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Purpose: Dysregulated expression of steroid receptor transcriptional coactivators and corepressors has been implicated in tamoxifen resistance, especially in estrogen receptor (ER) -positive breast cancer patients. Therefore, expression analysis of these ER coregulators may identify new predictors of the response to tamoxifen treatment.

Experimental Design: We measured mRNA levels of 16 coactivator and 11 corepressor genes with a real-time quantitative reverse transcription-PCR method in 14 ER-positive breast tumors. Three selected coactivator genes (TIF2, AIB1, and GCN5L2) and two corepressor genes (NCOR1 and MTA1L1) were additionally investigated in a well-characterized series of ER-positive unilateral invasive primary breast tumors from 99 postmenopausal patients who only received tamoxifen as adjuvant hormone therapy after primary surgery. We sought relationships between mRNA levels of the coregulators and those of molecular markers, including ER, ERß, CCND1, and ERBB2.

Results: ER coregulator expression was unrelated to age, histological grade, lymph node status, and macroscopic tumor size. The relationship between mRNA expression of the coregulators, and ER and ß only showed a significant positive correlation between GCN5L2 and ER (P = 0.015). mRNA levels of CCND1 correlated with those of all of the coregulators studied (P < 0.05 or trend), whereas ERBB2 mRNA levels only correlated with AIB1 mRNA levels (P = 0.011). Low NCOR1 expression (versus intermediate and high) was associated with significantly shorter relapse-free survival (log-rank test; P = 0.0076). The prognostic significance of low NCOR1 expression persisted in Cox multivariate regression analysis (P = 0.043).

Conclusions: These findings point to NCOR1 as a promising independent predictor of tamoxifen resistance in patients with ER-positive breast tumors.

	Introduction

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ER³ belongs to the superfamily of steroid nuclear receptor transcriptional factors. It regulates the proliferation and differentiation of many tissues, especially reproductive tissues (1) . On binding to specific DNA sequences such as EREs, estrogen-ER complexes activate or repress target gene transcription. The biological activity of estrogen is now realized to be more complex than initially thought, with the discovery of a second ER named ERß (2) . The ER-mediated transcriptional activity of estrogen is influenced by several regulatory factors known as coactivators and corepressors, which activate or repress the transcription of ER-responsive genes (1) . Up to now, the enhancer activity of these coregulators has mainly been studied with ER, but it may differ between the two ERs, providing additional regulatory steps in estrogen signaling (3) . Transcriptional activation is triggered, via histone acetyltransferase activity, by protein-protein interactions between the receptor and cofactors, and also through interactions with the SWI/SNF chromatin remodeling complex; together, these mechanisms result in nucleosome disruption and allow RNA polymerase complex transcription activity to take place (4) . Transcription silencing is also based on protein-protein interactions, this time between the receptor and corepressors, the latter belonging to larger protein complexes with histone deacetylase activity, which promotes nucleosome condensation (5) .

Tamoxifen is the most common endocrine agent used at all stages of breast cancer and particularly for the treatment of postmenopausal patients. ER status has been used to identify breast cancer patients who are likely to respond to tamoxifen, but resistance nonetheless occurs in 50% of treated ER-positive breast cancer patients (6) . This tamoxifen resistance could be because of dysregulation of ER coregulator expression in breast tumors (7) . Indeed, in addition to the competitive antagonistic effect of tamoxifen for the ER ligand-binding site, the main mechanism underlying the antiproliferative activity of this drug (8) , tamoxifen could also inhibit cell proliferation by promoting apoptosis, as shown in vitro and in vivo (9 , 10) . Tamoxifen-induced apoptosis may be associated with the recruitment of coregulators, which do not normally interact with estrogen-ER complexes, leading to abnormal transcriptional regulation of ER target genes (11) .

To identify the ER coregulators involved in tamoxifen resistance, we used real-time quantitative RT-PCR assays to analyze the expression of a large panel of coregulators (16 coactivators and 11 corepressors; Table 1 ) in 14 ER-positive breast tumors. We then additionally investigated five coregulators of interest, comprising three coactivators, TIF2 (12) , AIB1 (13) , and GCN5L2 (14) and two corepressors, NCOR1 (15) and MTA1L1 (16) , in a well-characterized series of 99 ER-positive unilateral invasive primary breast tumors from postmenopausal patients who exclusively received tamoxifen as adjuvant hormone therapy after primary surgery. Relationships between the mRNA levels of these coregulators, and clinical and pathological parameters, including RFS, were then studied. Finally, we sought relationships between mRNA levels of the coregulators and those of well-known molecular markers in breast cancer (ER, ERß, and PR), and two candidate predictors of the response to endocrine therapy, CCND1 (17) and ERBB2 (18) , of which the expression has been shown recently to be regulated by ER coactivator genes (19 , 20) .

View this table: [in this window] [in a new window]   Table 1 Coregulator genes mRNA levels in 14 ER-positive breast tumors

	Materials and Methods

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The patients (mean age, 70.7 years; range, 54–86) met the following criteria: primary unilateral ER-positive nonmetastatic postmenopausal breast carcinoma; complete clinical, histological, and biological information available; no radiotherapy or chemotherapy before surgery; and full follow-up at Centre René Huguenin. The histological type and the number of positive axillary nodes were established at the time of surgery. The malignancy of infiltrating carcinomas was scored according to the histoprognostic system of Bloom and Richardson (21) . ER-positive status was determined at the protein level by using biochemical methods (dextran-coated charcoal method until 1988 and enzymatic immuno-assay thereafter) and confirmed by ER real-time quantitative RT-PCR assay. Standard prognostic factors are reported in Table 2 . Thirty patients had modified radical mastectomy, and 69 had breast-conserving surgery plus locoregional radiotherapy. The patients underwent physical examinations and routine chest radiography every 3 months for 2 years, then annually. Mammograms were done annually. The median follow-up was 6 years (range, 1.5–17.5 years). All of the patients received postoperative adjuvant endocrine therapy (tamoxifen, 20 mg daily for 3–5 years) and no other treatment. Thirty-three patients relapsed. The first relapse events consisted of local and/or regional recurrences in 3 patients, metastases in 26 patients, and both events in 4 patients.

View this table: [in this window] [in a new window]   Table 2 Characteristics of the 99 postmenopausal patients with ER-positive breast tumors and relation to RFS

Real-Time RT-PCR
Theoretical Basis.
Reactions are characterized by the point during cycling when amplification of the PCR product is first detected, rather than the amount of PCR product accumulated after a fixed number of cycles. The higher the starting quantity of the target molecule, the earlier a significant increase in fluorescence is observed. The parameter Ct is defined as the fractional cycle number at which the fluorescence generated by SYBR Green dye-amplicon complex formation passes a fixed threshold above baseline.

The precise amount of total RNA added to each reaction mix (based on absorbance) and its quality (lack of extensive degradation) are both difficult to assess. Therefore, we also quantified transcripts of the gene coding for the TBP (a component of the DNA-binding protein complex TFIID) as the endogenous RNA control and normalized each sample on the basis of its TBP content (22) .

The relative target gene expression level was also normalized to the expression in the breast tumor sample (calibrator) from the two series (n = 14 or n = 99), which contained the smallest amount of target gene mRNA.

Final results, expressed as N-fold differences in target gene expression relative to the TPB gene and the calibrator, and termed "N target," were determined as follows: N target = 2^{(Ct calibrator - Ct sample)}, where Ct values of the calibrator and sample are determined by subtracting the Ct value of the target gene from the Ct value of the TBP gene.

Primers and PCR Consumables.
The primers for the chosen coregulator genes and TBP were chosen with the assistance of Oligo 4.0 software (National Biosciences, Plymouth, MN). We conducted BLASTN searches against dbEST and nr (the nonredundant set of the GenBank, EMBL, and DDBJ database sequences) to confirm the total gene specificity of the chosen nucleotide sequences and the absence of DNA polymorphisms. The primer nucleotide sequences for the 5 coregulator genes (and TBP) analyzed in the full panel of 99 breast tumors are shown in Table 3 ; the other coregulator gene primer sequences are available on request. The primer sequences for ER, ERß, PR, ERBB2, and CCND1 have been published elsewhere (22, 23, 24) . To avoid amplification of contaminating genomic DNA, one of the two primers was placed at the junction between two exons or in a different exon. For example, the upper primer of TBP was placed at the junction between exon 5 and 6, and the lower primer in exon 6.

cDNA Synthesis.
RNA was reverse-transcribed in a final volume of 20 µl containing 1x RT-PCR buffer [500 mM each deoxynucleotide triphosphate, 3 mM MgCl₂, 75 mM KCl, and 50 mM Tris-HCl (pH 8.3)], 10 units of RNasin RNase inhibitor (Promega, Madison, WI), 10 mM DTT, 50 units of Superscript II RNase H^- reverse transcriptase (Life Technologies, Inc.), 1.5 mM random hexamers (Pharmacia, Uppsala, Sweden), and 1 µg of total RNA (patient samples). Samples were incubated at 20°C for 10 min and 42°C for 30 min, and reverse transcriptase was inactivated by heating at 99°C for 5 min and cooling at 5°C for 5 min.

PCR Amplification.
All of the PCR reactions were performed using a ABI Prism 7700 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA).

For each PCR run, a master mix was prepared on ice with 1x SYBR Green buffer, 5 mM MgCl₂, 200 µM dATP, dCTP, and dGTP, and 400 µM dUTP, 300 nM each primer, and 1.25 units of AmpliTaq Gold DNA polymerase (Perkin-Elmer Applied Biosystems). Five µl of each diluted cDNA solution sample was added to 20 µl of the PCR master-mix. The thermal cycling conditions comprised an initial denaturation step at 95°C for 10 min, and 50 cycles at 95°C for 15 s and 65°C for 1 min.

	Statistical Analysis

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RFS was determined as the interval between initial diagnosis and detection of the first relapse (local and/or regional recurrence, and/or metastasis). Mean ER coregulator mRNA levels were compared by using the Kruskal-Wallis test. Spearman’s rank correlation test was used to study relationships between continuous variables. Survival distributions were estimated by using the Kaplan-Meier method (26) , and the significance of differences between survival rates was determined using the log-rank test. Multivariate analysis using Cox’s proportional hazards model was used to assess the independent contribution of each variable to RFS (27) . Differences between groups were judged significant at confidence levels >95% (P < 0.05).

	Results

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Expression Analysis of 27 Coregulator Genes in 14 ER-Positive Breast Tumors
We measured mRNA expression levels of 27 ER coregulator genes in a series of 14 ER-positive breast tumor samples (Table 1) . The widest ranges of values for a coactivator gene and a corepressor gene were, respectively, from 1 to 17.6 for TIF2 and from 1 to 15.5 for NCOR1. We then additionally studied selected genes in a larger series of 99 ER-positive breast tumors. The selection was based on: (a) the widest range of expression in the initial series of 14 breast tumor samples; (b) selection of two genes from each coactivator and corepressor type of genes; and (c) coregulator genes reported previously to be dysregulated in breast cancer (AIB1; Ref. 13 ).

Thus, we selected two coactivators that interact directly with ER (TIF2 and AIB1), a coactivator involved in nucleosome disruption (GCN5L2), a corepressor that interacts with ER (NCOR1), and a corepressor belonging to a histone deacetylase complex (MTA1L1).

Expression Analysis of Five Coregulator Genes in 99 Postmenopausal ER-Positive Breast Tumors
Coregulator mRNA Steady-State Levels in Breast Tumor Samples.
Table 4 shows the mean, median, and range of TIF2, AIB1, GCN5L2, NCOR1, and MTA1L1 mRNA levels in the 99 postmenopausal ER-positive breast tumors. The range of TIF2 and GCN5L2 expression exceeded 30-fold, whereas that of the other three coregulators did not exceed 20-fold.

View this table: [in this window] [in a new window]   Table 4 Mean, median, and range of coregulator genes mRNA levels in 99 ER-positive breast tumors

View this table: [in this window] [in a new window]   Table 5 Relationships between coregulator genes mRNA levels in 99 ER-positive breast tumors

View this table: [in this window] [in a new window]   Table 6 Relationships between coregulator genes mRNA levels and clinical, pathological, and molecular parameters in ER-positive breast tumors of 99 postmenopausal patients

Relationships between Coregulator and ER, ERß, PR, CCND1, and ERBB2 mRNA Levels.

ER

ER

ER

Prognostic Value of Coregulator mRNA Levels.
For the prognostic analysis of each gene, the patient population was divided into tertiles (three groups of 33), corresponding to low, intermediate, and high mRNA levels. Only NCOR1 showed prognostic value. Five-year RFS rates were 58.7% (49.8–67.6%) in the subgroup of low NCOR1 mRNA levels, and 80.8% (73.7–87.9%) and 83.1% (76.1–90.1%) in the subgroups with intermediate and high mRNA levels, respectively. Given the similar values in the subgroups with intermediate and high NCOR1 mRNA levels, we compared full follow-up RFS between the low NCOR1 subgroup (33 patients) and the combined intermediate and high subgroups (66 patients). Univariate analysis (log-rank test) showed that the outcome of the former 33 patients was significantly worse than that of the remaining 66 patients (P = 0.0076; Fig. 1 ).

View larger version (15K): [in this window] [in a new window]   Fig. 1. RFS in the patient subgroup with low NCOR1 mRNA levels (33 patients), and the combined subgroups with intermediate and high NCOR1 mRNA levels (66 patients).

	Discussion

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mRNA levels of the three coactivators correlated positively with one another as well as mRNA levels of the two corepressor genes (Table 5) . Positive correlations were also observed in all of the pairwise comparisons of the coactivators and corepressors, except for AIB1 with NCOR1 and GCN5L2 with MTA1L1. These correlations may be explained by: (a) transcriptional activation of all five of the genes by a common regulatory pathway; (b) specific up-regulation of one coactivator directly involved in transcriptional activation of the correlated coactivator and/or corepressor; and (c) up-regulation of corepressors aimed at controlling coactivators overexpression.

With respect to clinical and pathological parameters, ER coregulator expression was unrelated to age, histological grade, lymph node status, and macroscopic tumor size (Table 6) . Previous studies of breast tumors have shown a significant relationship between AIB1 overexpression and high tumor grade (30) , and also higher TIF2 expression levels in node-positive than node-negative breast tumors (31) . These discrepancies with our study could be explained in large part by differences in the study populations. Indeed, we studied a well-defined series of postmenopausal patients with ER-positive tumors.

The only significant relationship between ER coregulator gene expression, and ER and ERß expression was a positive correlation between GCN5L2 and ER, suggesting an interaction between the transcriptional regulation of the two genes, despite the lack of a consensus ERE sequence in the promoter region of the GCN5L2 gene (data not shown). Expression of the TIF2 coactivator and the NCOR1 corepressor was significantly linked to expression of the PR gene, which contains an ERE element in its promoter, suggesting a predominant role of these two genes in the transcriptional regulation of ER-responsive genes mediated by ERE.

It has been shown recently that transcriptional regulation of two candidate predictors of the response to endocrine therapy, the genes CCND1 and ERBB2, can be exerted by ER coactivators, despite the lack of an ERE in the promoter region of the two genes (19 , 20) . AIB1 was found to enhance CCND1 expression when incubated with estrogen, whereas antiestrogen treatment had no activating or inhibiting effect on CCND1 transcription. In our study, significant positive correlations were observed between mRNA expression of CCND1 and that of all of the coregulators but only a trend toward significance with AIB1, suggesting that AIB1 is not a major coactivator involved in CCND1 transcriptional regulation during breast tumorigenesis. Regarding the ERBB2 gene, Newman et al. (20) showed that p160 coactivators (of which AIB1 is a member) can modulate its enhancer activity. In our series, ERBB2 mRNA levels correlated significantly with AIB1 mRNA levels but not with the other four ER coregulators. The same relationship was reported at the protein level by Bouras et al. (30) , who found that tumors overexpressing AIB1 showed strong ERBB2-positive staining. These results suggest that transcriptional coactivators may establish cross-talk between ERE-dependent and -independent metabolic pathways involved in breast tumorigenesis.

The breast tumor samples studied here were obtained from a well-characterized series of patients treated exclusively with tamoxifen as adjuvant endocrine therapy. Therefore, we were able to evaluate the potential of the five selected ER coregulator genes as predictors of tamoxifen resistance. The hypothesis of NCOR1 being a potential marker of antiestrogen hormonotherapy (32) is conceivably related to in vitro studies that have established that NCOR1 protein binds ER (whether or not the interaction is tamoxifen-dependent is controversial; Refs. 33, 34, 35 ), and inhibits the partial agonistic activity of tamoxifen and its physiological metabolite (4-hydoxy-tamoxifen; Refs. 35 , 36 ). Likewise, in a mouse model of breast cancer, decreased NCOR1 protein expression correlated with acquired tamoxifen resistance (33) .

In human breast tumors, Chan et al. (37) did not show significant difference in the level of SMRT mRNA (a corepressor related to NCOR1) between tamoxifen-resistant breast tumor samples and untreated patients. Conversely, Kurebayashi et al. (31) found higher NCOR1 expression levels in tumors from patients without recurrence compared with patients with recurrence supporting its role as a tamoxifen resistance mechanism in vivo.

Here, we found that NCOR1 mRNA expression status (low versus intermediate and high) was associated with shorter RFS (log-rank test; P = 0.0076), and this prognostic significance persisted in Cox multivariate regression analysis (P = 0.043). Nevertheless, validation of the predictive value of NCOR1 parameter in the response to tamoxifen endocrine therapy in breast cancer patients needs a prospective randomized study to show that this parameter does influence the outcome only in patients who received adjuvant tamoxifen compared with untreated patients.

We showed previously, in the same patients series, that ERBB2 overexpression was a marker of poor prognosis (28) . By combining NCOR1 and ERBB2 expression status, we identified four separate prognostic groups. The patients with the best prognosis had high NCOR1 expression and normal ERBB2 expression (log-rank test; P = 0.00064), suggesting that the analysis of the two molecular markers together, affecting tamoxifen efficiency, may provide a more accurate prediction of hormone responsiveness (38) .

In conclusion, NCOR1 emerged from a series of 27 ER coregulator genes as a promising independent prognostic marker of tamoxifen resistance in patients with ER-positive breast tumors. Therefore, NCOR1 real-time RT-PCR assay should be valuable in the breast cancer clinical setting to better assess endocrine treatment efficiency.

	ACKNOWLEDGMENTS

 
We thank the staff of Centre René Huguenin for assistance with specimen collection and patient care. We also thank Dr. Kamel Hacène (Département de Statistiques Médicales, Centre René Huguenin, St-Cloud, France) for his helpful contribution.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Comité Régional des Hauts-de-Seine de la Ligue Nationale Contre le Cancer.

² To whom requests for reprints should be addressed, at Laboratoire d’Oncogénétique, Institut National de la Santé et de la Recherche Médicale E0017, Centre René Huguenin, 35 rue Dailly, F-92211 St-cloud, France. Phone: 33-1-47-11-15-66; Fax: 33-1-47-11-16-96; E-mail: i.bieche{at}stcloud-huguenin.org

³ The abbreviations used are: ER, estrogen receptor; ERE, estrogen-responsive element; RT-PCR, reverse transcription-PCR; TIF2, transcriptional intermediary factor 2; AIB1, augmented in breast cancer 1; GCN5L2, general control of amino acid synthesis, yeast, homologue-like 2; NCOR1, nuclear receptor corepressor 1; MTA1L1, metastasis-associated 1-like 1; PR, progesterone receptor; Ct, cycle threshold; TBP, TATA box-binding protein; RFS, relapse-free survival.

⁴ F. Spyratos, M. Labroquère, M. Tubiana-Hulin, S. Tozlu, M. Vidaud, K. Hacène, R. Lidereau, V. Becette, and I. Bièche. Expression of estrogen receptor beta mRNA in postmenopausal primary breast cancer patients receiving adjuvant tamoxifen, submitted for publication.

Received 4/16/02; revised 9/ 6/02; accepted 9/16/02.

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