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Human Cancer Biology |
-Negative Breast CarcinomaAuthors' Affiliations: Departments of 1 Oncology and 2 Theoretical Physics, Lund University, Lund, Sweden; 3 Institute for Cancer Genetics, Columbia University, New York, New York; 4 Institute of Medical Technology, University of Tampere, Tampere, Finland; and 5 Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, Finland
Requests for reprints: Sofia K. Gruvberger-Saal, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Irving Cancer Research Center, Suite 406, New York, NY 10032. Phone: 212-851-5263; Fax: 212-851-5267; E-mail: sg2414{at}columbia.edu.
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)–positive breast carcinoma but are not indicated for persons with ER-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ER-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERß, in patients treated with adjuvant tamoxifen. Experimental Design: We investigated ERß by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.
Results: ERß was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ER-negative patients (P = 0.003; P = 0.04), but not in the ER-positive subgroup (P = 0.49; P = 0.88). Lack of ERß conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ER-negative subgroup even after adjustment for other markers. ER was an independent marker only within the ERß-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERß gene expression profile was identified and was markedly different from the ER signature.
Conclusion: Expression of ERß is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ER-negative breast cancer patients and involves a gene expression program distinct from ER. These results may be highly clinically significant, because in the United States alone, 
10,000 women are diagnosed annually with ER-negative/ERß-positive breast carcinoma and may benefit from adjuvant tamoxifen.
and ß (1–3), which function as transcription factors and modulate the expression of target genes in response to estrogens. The biology of ER has been studied for decades and evaluation of tumor ER content is a mainstay of clinical practice as a marker associated with prognosis and response to endocrine therapies such as tamoxifen (4).
Tamoxifen is a selective ER modulator and is the most frequently prescribed drug for treatment of breast cancer. Tamoxifen is known to inhibit estrogen-stimulated growth of breast cancer cells by competitively binding to and blocking ER (4). Patients with tumors lacking ER in general do not benefit from tamoxifen therapy, although a fraction of ER-negative tumors do seem to be sensitive to tamoxifen (5–7). The factors responsible for these responders are debated and no means of identifying this group is currently known. Therefore, tamoxifen is not indicated for patients with ER-negative tumors in the adjuvant or metastatic setting.
Since the discovery of ERß (3), which has a similar binding affinity as ER for estrogens (8), several studies have focused on its biological function in relation to ER. The two ER proteins share a high degree of homology in the DNA-binding regions but differ considerably in the NH2-terminal activation function 1 region, where interactions with other proteins in the transcriptional machinery takes place, and to a certain degree in the ligand-binding region (9), indicating that these receptors may share some similar functions but may not be entirely redundant. Indeed, they have been shown to respond differently in ligand-induced activation at activator protein 1 sites (10). In addition, ER and ERß can exist as a heterodimer (11–13), suggesting a possible role for ERß as a modulator of ER activity.
Recently, several studies have measured ERß in breast cancer specimens and sought to clarify the relationship between ERß and other clinicopathologic features and its role in response to endocrine treatment; however, some of the results have been conflicting and most focused on ERß as a resistance marker in ER-positive tumors (refs. 14–16, and those reviewed in ref. 17). ERß has been shown to bind tamoxifen (18), and it has been suggested that low levels of ERß associates with tamoxifen resistance (14). Conversely, Hopp et al. (15) showed that expression of ERß had a beneficial effect on disease-free and overall survival in a group of 186 tamoxifen-treated tumors; however, they found no such association in their set of 119 untreated patients, suggesting a role for ERß as a predictive marker for tamoxifen sensitivity but not as a prognostic marker. Importantly, the patients studied by Hopp et al. (15) were predominantly ER-positive and the numbers were limited; thus, they were unable to perform an analysis stratified by ER status. To our knowledge, no study has investigated the role of ERß as a predictive marker for tamoxifen response for patients with ER-negative tumors.
In the present report, we investigated ERß protein levels as predictor of therapy response in a large patient set, including both ER-positive and ER-negative tumors all treated uniformly with 2 years of adjuvant tamoxifen. Furthermore, we sought to identify a gene expression signature for ERß status and compare it with the ER-associated expression signature.
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Determination of other tumor markers. Steroid receptor protein [ER and progesterone receptor (PgR)] determinations using enzyme immunoassay (22), and flow cytometric analysis of S-phase fraction and DNA ploidy analysis (23), were done as part of the routine tumor evaluation. ER and PgR status, S-phase fraction status, and DNA ploidy status were classified as previously described (22, 24). ERBB2 amplification was measured using chromogenic in situ hybridization analysis (25).
Statistical analysis. The 
2 test for association and 2 test for trend, Mann-Whitney U test, and Kruskal-Wallis test were used to assess associations between tumor ERß or ER content and other variables. All factors were used as categorized variables in the statistical analysis except for age, which was also analyzed as a continuous variable. The Kaplan-Meier method was used to estimate distant disease-free survival and overall survival and the log-rank test was used to compare survival between two strata. The log-rank test for trend was used to compare survival in more than two strata. To test whether the effects on distant disease-free survival of ER and ERß changed significantly with time, Schoenfeld's test for time dependence was applied. The association of the level of ERß with patient outcome, adjusted for other prognostic factors and for interaction between ERß and ER, was assessed in a multivariate analysis using Cox proportional hazards model. All tests were two-sided and P values <0.05 were considered significant. Statistical analyses were carried out using Stata 8.0 (Stata Corporation, College Station, TX).
Microarrays. cDNA microarrays with 27,648 spots were produced in the SWEGENE Microarray Facility, Department of Oncology, Lund University. The gene set consisted of 24,301 sequence-verified IMAGE clones (Research Genetics, Huntsville, AL) and 1,296 internally generated clones, together representing 
15,000 UniGene clusters (build 180) and 1,200 unclustered expressed sequence tags, and were PCR amplified using vector-specific primers essentially as previously described (26) with some modifications. Tissue processing for the 88 breast tumor samples, RNA labeling, and microarray hybridization protocols are described in detail in Supplementary Materials and Methods.
Microarray data analysis. Microarray data are available through National Center for Biotechnology Information Gene Expression Omnibus,6 accession no. GSE6577. The ERß+ and ERß++ tumors were grouped together and analyzed as a single ERß-positive (ERß+/++) entity. Thus, the distribution of the 88 tumors between the four ER/ERß groups was as follows: 10 ER–/ERß–, 36 ER–/ERß+/++, 8 ER+/ERß– and 34 ER+/ERß+/++.
Data analysis was done using BioArray Software Environment (27). Data preprocessing and filtering procedures, described in the Supplementary Materials and Methods, left 10,493 informative genes. The genes were ranked based on the signal-to-noise statistic (28), which calculates a correlation score between gene expression and the tumor annotation of interest. To evaluate the significance of the expression signatures between two annotation classes (e.g., ERß status), 1,000 permutations were run whereby the samples were randomly given an annotation label and the P value for a score was calculated as the average number of reporters exceeding the score in the permutation test, divided by the total number of reporters in the gene list. The false discovery rate (FDR) was calculated by random permutations, controlled according to Benjamini et al. (29), and used as an indicator of the robustness of the gene expression profile. An FDR of 0% indicates no false positives, whereas an FDR of 100% indicates complete random signal. To test the dependence of FDR on number of samples for the ERß analysis in the two ER status subgroups, two ERß-negative and two ERß-positive samples were randomly removed from the ER-negative cohort, making both these two groups equal in size to the corresponding groups in the ER-positive cohort. For the reduced ER-negative data set, genes were ranked and FDRs based on 1,000 permutations were calculated; the procedure was repeated 200 times with different random selections of removed samples. The Significance Analysis of Microarrays algorithm (30) implemented in TIGR Multiexperiment Viewer 3.1 (31) with 1,000 permutations and default settings was also used to generate comparative FDR plots. Hierarchical clustering and data visualization are described in the Supplementary Materials and Methods.
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positive, and the association between the expression of ERß and ER was nonsignificant (P = 0.18). Although ER positivity was associated with several clinical variables such as increasing age (P = 0.003), postmenopausal status (P = 0.007), a greater number of lymph nodes with metastases (P = 0.006), PgR positivity (P < 0.001), a low S-phase fraction (P < 0.001), and nonamplified ERBB2 (P < 0.001), ERß expression did not correlate significantly with any of the clinical variables tested (Table 1). In a subgroup analysis, increasing ERß level was associated with high S-phase fraction within the ER-negative group (P = 0.03) but not with any other markers (data not shown).
Analysis of distant disease-free survival. Among all cases, ERß expression was significantly associated with an increased distant disease-free survival (P = 0.01; Fig. 1A
). When stratified by ER status, ERß level was significantly associated with better distant disease-free survival (P = 0.003) in the ER-negative group (Fig. 1B). A multivariate Cox regression analysis of distant disease-free survival, including lymph node status, menopausal status, tumor size, ERBB2 amplification, ER status, two dummy variables for ERß– (versus ++ and + versus ++), and two interaction terms for ERß with ER status (Table 2
) showed a significantly worse distant disease-free survival for the ERß– group compared with ERß++ in the ER-negative subgroup, with a hazard ratio (HR) of 14 [95% confidence interval (95% CI), 1.8-106; P = 0.01]. Between the ERß+ and ERß++ groups in the ER-negative subgroup, there was a similar but nonsignificant trend (HR, 6.1; 95% CI, 0.79-46; P = 0.08). In contrast, as extrapolated from the model presented in Table 2, there was no effect of ERß on distant disease-free survival in the ER-positive group (Fig. 1C), neither between the ERß and ERß++ groups (HR, 1.2; 95% CI, 0.57-2.5; P = 0.70) nor between the ERß+ and ERß++ groups (HR, 1.0; 95% CI, 0.05-2.0; P = 1.00). The Cox regression model also showed that the effect of ERß++ status (compared with ERß–) was significantly different in the two ER subgroups (P = 0.02; Table 2).
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-dependent effect for ERß, we tested for the inverse dependency: The correlation of ER status with distant disease-free survival in the whole patient group and in the different ERß subgroups (Fig. 1D-G). Interestingly, using the Kaplan-Meier method and log-rank test, ER was significantly associated with a better prognosis exclusively in the ERß– subgroup (P = 0.05; Fig. 1E) but not in the whole cohort or any of the other ERß subgroups (Figs. 1D and F-G, respectively). From the Cox regression model with interaction between ER and ERß (Table 2), the predictive value of ER for distant disease-free survival in the different ERß subgroups could be interpreted. In agreement with the results from the Kaplan-Meier analysis, we found that ER positivity was a significant independent predictive marker for improved distant disease-free survival only within the ERß– group (HR, 0.44; 95% CI, 0.21-0.89; P = 0.02), whereas no significant effect was seen in the other two subgroups (ERß+: HR, 0.86; 95% CI, 0.45-1.7; P = 0.70; ERß++: HR, 5.2; 95% CI, 0.67-40; P = 0.12).
The effect of ERß on distant disease-free survival in the ER-negative group did not change significantly with time (P = 0.21; Schoenfeld's test), whereas the effect of ER expression on distant disease-free survival in the ERß– group proved to be time dependent (P = 0.005) and diminished over a long follow-up time. Furthermore, as the distributions of ER and PgR concentrations between the ERß subgroups within the ER-negative tumors were similar (P = 0.68 for ER and P = 0.41 for PgR, Kruskal-Wallis test), we concluded that residual low levels of ER or PgR protein in the three ERß subgroups did not contribute to the prognostic effect of ERß within the ER-negative tumors.
In addition to ERß++ status compared with ERß– in the ER-negative subgroup, four or more lymph nodes (compared with 0) and menopausal status had independent prognostic value after tamoxifen treatment in the multivariate analysis (Table 2). No other effects were significant; however, ERBB2 amplification and ERß+ status (compared with ERß++) in the ER-negative subgroup showed a tendency (P < 0.10) to carry prognostic information (Table 2). S-phase fraction, age as a continuous variable, PgR, and DNA ploidy status were not included in the multivariate analysis as they showed no significant association with distant disease-free survival in univariate analysis.
Analysis of overall survival. Using the Kaplan-Meier method and log-rank test, a beneficial effect of ERß positivity on overall survival was seen among ER-negative tumors (P = 0.04; Fig. 1I) but not in the whole tumor group (P = 0.22; Fig. 1H) or among ER positives (P = 0.88; Fig. 1J).
Gene expression analysis. The ERß gene expression signature in the 88 patients, representative of the original cohort (data not shown), had an FDR of 49% per top 100 discriminator genes ranked by the signal-to-noise ratio analysis score (28), and 50% per top 500 genes, indicating that ERß was associated with a unique, albeit weak, expression profile. The ER status–associated gene expression signature from this data set had no false-positive genes in the top 1,000 genes. When stratified by ER, ERß was associated with a detectable expression profile within the ER-negative group (FDR of 40% per top 100 discriminator genes, and 43% per top 500; Fig. 2
); however, there was no signal in the ER-positive group (FDR reached >90% by the top 10 genes; Fig. 2). A similar difference in gene expression signature strength was seen when using the Significance Analysis of Microarrays algorithm (30) to generate FDR curves (data not shown).
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-positive tumors was due to the ERß signal being masked by the much stronger ER-associated profile, we used the top 50 and top 100 ERß genes generated from the ER-negative subgroup and tested whether they could separate the tumors according to ERß status within the ER-positive subgroup using hierarchical clustering analysis. The resulting tumor dendrogram showed a scattered distribution not correlating to ERß levels (data not shown), whereas using these genes within the ER-negative group displayed ERß-associated tumor clusters (result for the top 50 ERß genes are shown in Fig. 3
). The successful ERß discrimination in the ER negatives was not due to a difference in distribution of residual ER concentration in the ERß groups, because the distribution of ER values in the three ERß subgroups within the ER-negative tumors were similar (P = 0.75) as were the distribution of PgR concentrations (P = 0.58). Moreover, the ERß signal in ER-negative tumors was still present even when top 400 ER signature genes were removed before identifying the ERß signature (FDR of 42% per top 100 genes).
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-positive group was due to the lower number of samples in this group compared with the ER-negative group (42 ER positives versus 46 ER negatives), samples were randomly removed from the ER-negative cohort, to make the two ERß groups equal in size to the corresponding groups in the ER-positive cohort. In none out of the 200 randomly reduced ER-negative cohorts was the FDR, for top 10 up to top 1,000 genes or more, equal to or larger than that of the ER-positive cohort, indicating that the difference in ERß signal strength in the two ER subgroups is robust.
We compared the extent of overlap of genes comprising the ERß and ER expression signatures. The two expression profiles generated from all 88 cases were substantially different: No genes were overlapping among the respective top 100 ranked genes; moreover, among the top 1,000 ranked genes, the overlap was only 6%. The ERß signature generated from within the ER-negative tumors, which could be considered a "purer" ERß profile, showed a similar degree of nonoverlap with the ER gene list from all cases: 1% in top 100 and 7% in top 1,000.
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status–specific survival benefit of ERß expression in tamoxifen-treated breast cancer patients. In light of a previous study showing no prognostic value of ERß in untreated patients (15), our results suggest that ERß is a predictive marker for response to tamoxifen in ER-negative patients.
Although ER positivity is a well-established predictor of response to tamoxifen and ER-negative patients are considered nonresponders, it has been noted that 5% to 10% of ER-negative tumors do benefit from adjuvant tamoxifen (5–7). Several theories have been put forward to explain these cases: Failures or inconsistencies in the performance or evaluation of ER measurements result in miscategorization of what are actually ER-positive tumors, or that tamoxifen acts through mechanisms independent of ER. Our results support the latter and suggest that an ER-independent alternative mechanism of action of tamoxifen is via ERß (of note, 17% of ER-negative tumors were strongly positive for ERß). Furthermore, there was a similar distribution of ER and PgR protein values in the three ERß subgroups within the ER-negative tumors, suggesting that misclassification of ER-positive tumors did not confound our results.
Although ER did not have significant predictive value for tamoxifen response in the entire patient group over the complete long follow-up period, ER was predictive within the ERß-negative group (P = 0.05, Fig. 1E; HR, 0.44; 95% CI, 0.21-0.89; P = 0.02, extrapolated from Table 2). Moreover, it appeared that ER negativity may confer a better outcome within the ERß strongly positive group (P = 0.09, Fig. 1G; HR, 5.2; 95% CI, 0.67-40; P = 0.12, Table 2). These findings raise an intriguing hypothesis that the best tamoxifen response is achieved when a tumor is expressing either ER or ERß, but not both. A biological explanation for this could be that the two receptors modulate the function of each other, so that when coexpressed the effect of tamoxifen becomes less pronounced or, alternatively, is growth promoting. This postulation is supported by the following observations: The two receptors can be coexpressed within individual breast carcinoma cells (33); they can form heterodimers (11–13); ERß can function as an inhibitor of ER activity under certain conditions (34); and when coexpressed with ER, ERß has been suggested to be associated with tumor characteristics indicative of a poorer prognosis (35).
Despite the similar utility of ERß or ER as markers for benefit from tamoxifen therapy in this study group, the two receptors show many dissimilarities. Within all cases, ER expression correlates strongly with the majority of other standard clinicopathologic markers, whereas ERß expression did not, corroborating the results of recent studies (15, 16). ERß did, however, correlate with high S-phase fraction within the ER-negative group, which is consistent with the literature showing an association between ERß and the proliferation marker Ki67 (16, 36). An ERß-dependent high proliferation rate of these tumor cells may render them more sensitive to tamoxifen therapy (37).
We have previously shown that ER status in breast cancer is associated with a robust gene expression signature (38), and the most readily apparent subdivision of breast cancers based on gene expression data is according to ER status (39, 40). The present study is the first to identify an ERß-associated gene expression profile in human tumor biopsies. The lack of ERß-associated signal in ER-positive tumors suggests that ERß seems to be less influential on gene expression, and hence tumor biology, in cancers also expressing ER. However, this does not necessarily rule out that ERß under certain conditions can have some modulating effect on ER. Our results indicate that the ERß gene expression signature was markedly different from the ER gene expression signature as the genes included in the two profiles showed minimal overlap. However, due to the limited sample size in this study, these findings call for further validation in data sets including larger number of tumors. Together, our data suggests that ERß, in the absence of ER, is not simply a surrogate marker for ER, but rather ERß may affect growth and proliferation of breast cancer cells through modulation of different downstream target genes.
As far as we are aware, this is the largest survival study of ERß in breast cancer specimens to date. It will be important to confirm our results in other cohorts containing large numbers of ER-negative tumors treated uniformly with tamoxifen. It remains to be tested whether a predictive effect of ERß exists for patients treated with other selective ER modulators or other types of endocrine therapies, such as aromatase inhibitors. Moreover, analysis of large series of untreated patients is necessary to confirm that ERß does not have prognostic value (15) and is specifically a predictive marker for therapeutic response to tamoxifen. In this regard and suggesting that the ERß benefit may indeed be related to antiestrogen therapy, a recent study of ER-negative breast tumor patients that received varied therapies (<35% received unspecified hormonal therapies alone or in combination) found no recurrence-free survival benefit for ERß expression (16).
In the present study, we categorized ERß status into three groups with the goal of understanding the influence of different levels of ERß expression on survival for tamoxifen-treated patients. Further refinement will be needed to identify optimal and standardized methods for determining ERß content, scoring, and thresholds, and whether different ERß variants modulate response dissimilarly.
From our data, it can be estimated that in the United States alone, 10,000 patients per year will be diagnosed with ER-negative/ERß-positive breast carcinoma. Given the relatively low toxicity and cost of tamoxifen, our results have striking clinical implications that motivate further studies to explore the efficacy of tamoxifen to treat ER-negative/ERß-positive breast tumors.
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Acknowledgments |
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Footnotes |
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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.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Current address for S.K. Gruvberger-Saal: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
6 http://www.ncbi.nih.gov/geo/ 
Received 7/24/06; revised 12/22/06; accepted 1/ 3/07.
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and ß. Endocrinology 1997;138:863–70. and ERß at AP1 sites. Science 1997;277:1508–10. and ß form heterodimers on DNA. J Biol Chem 1997;272:19858–62.. Mol Endocrinol 1997;11:1486–96. in vivo and in vitro. Biochem Biophys Res Commun 1998;243:122–6.[CrossRef][Medline] negative human breast tumours. Br J Cancer 2006;95:616–26.[CrossRef][Medline] transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999;140:5566–78. and ß: poor prognostic factors in human breast cancer? Cancer Res 1999;59:525–8.This article has been cited by other articles:
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