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Molecular Oncology, Markers, Clinical Correlates |
1 Department of Cancer Medicine, Cancer Cell Biology Group, Cancer Research UK Laboratories, Imperial College-London, Hammersmith Hospital, London, United Kingdom; 2 Department of Medical Oncology, St. George’s Hospital, London, United Kingdom; 3 Department of Histopathology, Imperial College Faculty of Medicine and Charing Cross Hospital, London, United Kingdom; 4 Department of Social Science and Medicine, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, London, United Kingdom; and 5 Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge, Sweden
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-positive breast cancer is often treated with endocrine therapy using either antiestrogens or aromatase inhibitors. However, 30% of patients who receive endocrine therapy will derive no benefit from such treatments and may indeed suffer adverse effects. Currently, there are no ways to predict response to such treatments. ERßcx, a variant of ERß, has a dominant-negative effect over ER, and its expression thought to modulate response to endocrine treatment may represent a predictor of response to endocrine therapy. Experimental Design: We investigated the expression of the ERßcx in 82 frozen breast samples (8 benign, 1 ductal carcinoma in situ, and 73 malignant) by Western blot analysis. The relationship between the expression of ERßcx variants with prognosis and outcome of endocrine therapy was examined.
Results: There was a statistically significant association between the presence of ERßcx and the response to endocrine therapy (Fisher’s exact test, P = 0.04). We also examined the influence of the ERßcx status of a tumor on time to progression and death. There was a relationship between the presence of ERßcx and survival, with patients whose tumors express ERßcx having a longer survival rate (P = 0.05). Cell-type specificity of expression was assessed by immunohistochemistry on a selection of histological samples.
Conclusions: On the basis of this small group of patients, we conclude that the expression of ERßcx correlated with favorable response to endocrine therapy. A larger study involving the staining of archival material is currently underway to confirm these preliminary results.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and progesterone receptor (2, 3, 4)
. However, the predictive value of ER is not perfect, because 
30% of metastatic ER-positive tumors fail to respond to endocrine therapy (5)
. An improvement in the ability to predict the outcome of response to endocrine therapy would prevent patients from receiving inappropriate treatment and could also enhance the prognostic stratification of ER-positive patients.
ER and ERß represent distinct gene products, and have 96% and 60% homology in the DNA-binding domains and ligand-binding domains, respectively (6
, 7)
. Since the initial cloning of ERß, several splice variants of this receptor have been identified in humans and other species (6, 7, 8, 9, 10, 11, 12, 13)
; however, the role of ERß in breast cancer is still unclear. Leygue et al. (14)
found that those tumors coexpressing ER and ERß were node positive and tended to be of a higher grade, whereas Jarvinen et al. (15)
proposed that ERß was often associated with lower-grade tumors and negative axillary node status. A decreased expression of ERß in proliferative preinvasive tumors has been reported (16)
, whereas Speirs et al. (17)
found that ERß was increased in expression in tamoxifen-resistant tumors. ERß expression has also been found to be associated with elevated levels of the proliferation markers Ki67 and cyclin A, especially in recurrent cancers (18)
. A novel human ERß variant, which is truncated at the COOH terminus, was identified in 1998 by the screening of a human testis cDNA library (19)
. It was named hERßcx by Ogawa et al. (19)
and hERß2 by Moore et al. (20)
, and will be referred to as ERßcx in the present study. The coding sequence of this variant was found to be identical to ERß cDNA except that the COOH-terminal 61 amino acids of ERß were replaced by a unique 26 amino acid sequence, resulting in a protein with 495 amino acids (Mr 55,000). The 61 amino acids that are replaced in ERßcx are encoded by exon 8 of the ERß gene, making up the AF-2 core, which is essential for ligand-dependent transcriptional activation. The ERßcx variant has been found to be expressed in ovary, testis, prostate, and thymus (19
, 21, 22, 23)
. Transfection of ERßcx expression constructs into COS cells did not reveal either detectable binding of estrogen in whole cell extracts or activation of an estrogen response element-containing reporter plasmid in either the presence or absence of estrogen (19
, 24)
. Consistent with the presence of both the DNA-binding and dimerization domains, mobility shift assays have shown that ERßcx binds to DNA containing an estrogen response element consensus sequence as a heterodimer with either ER and ERß1 (20)
. It was also found that ERßcx was unable to interact with TIF1, a co-regulator that interacts with ligand activated hER via the AF-2 domain (19)
. ERßcx preferentially forms heterodimers with ER and ERß; whereas ER is inhibited by ERßcx, ERß1 is unaffected, suggesting that ERßcx can act as a dominant-negative inhibitor of ER. In support of this notion, Tremblay et al. (25)
have shown that in mice ER and ERß lacking an intact AF-2 can impair transcriptional activity of the ER-ERß heterodimer.
The often contradictory results published regarding the role of ERß in breast cancer could be related to the presence or absence of a number of splice variants, which exert dramatically different biological effects, in particular ERßcx. ERß is known to be expressed in both normal and malignant breast tissue, and presence of ERßcx in breast cancer has been demonstrated by both PCR and Western blot of sucrose density gradients (26)
. In certain breast tumors, ERß was detected but there was no 4S estradiol binding peak in sucrose density gradients, and subsequent PCR revealed the presence of ERßcx. This observation using human breast tissues supports the results of the in vitro experiments of Ogawa et al. (19)
that ERßcx can dimerize with ER and negatively modulate its ligand-binding activity.
Consequently, we sought to determine the expression patterns of ERßcx in normal and malignant breast tissue to correlate this expression with clinical outcome. Frozen breast samples (82) were analyzed for ERßcx expression by Western blotting, and in a complementary approach, the cell-type specificity was analyzed by immunohistochemistry. The relationship between the expression of ERßcx variants with prognosis and outcome of endocrine therapy was also examined.
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MATERIALS AND METHODS |
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. Information on patient age, menopausal status, pathological diagnosis, and differentiation grade were recorded, and the notes reviewed for response to endocrine treatment.
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50% reduction in tumor size as determined by two measurements of tumor diameter or the product of two perpendicular diameters, at least 4 weeks apart. No change was defined as <50% tumor regression or <25% progression, and progressive disease as 25% increase in tumor measurements. Time to progression was defined as the time from initial diagnosis to documented date of first relapse, and time to death was defined as the time from initial diagnosis to death.
Preparation of Cell Lysates from Frozen Tissue Samples.
Frozen tissue samples were pulverized in a dismembrantor (Braun Melsungen, Melsungen, Germany) for 45 s at 1800 rpm. Pulverized tissue was added to a buffer composed of 10 mM Tris-HCl (pH 7.5), 1.5 mM EDTA, and 5 mM sodium molybdate, using 1 ml/100 µg tissue. Cytosol was obtained by centrifugation of the homogenate at 204,000 x g for 1 h in a 70Ti (Sorvall) rotor at 4°C.
Immunohistochemistry for ERßcx.
Immmunohistochemistry was performed on paraffin sections of breast tissue obtained from the histopathology archive at Charing Cross Hospital using a new anti-ERßcx sheep polyclonal antibody that recognizes the ERßcx-specific sequence (MKMETLLPEATMEQ) at the COOH terminus of ERßcx but not other ER variants; hence, this antibody is specific for ERßcx. The sections were also stained with a rabbit polyclonal protein A purified polyclonal antibody that reacts with the NH2-terminal region (YAPQKSPWCEARSLEHT, amino acids 46–63) of ERß (28)
, and this antibody recognized the majority of ERß isoforms. Two-µm paraffin sections were dewaxed in xylene and rehydrated through graduated alcohol to water. Antigen retrieval was performed by microwaving sections in 5% urea for 15 min at 800 W. Endogenous peroxidase was blocked by incubation for 30 min with a solution of 0.3% hydrogen peroxide at room temperature and washed twice for 5 min in PBS. Tissue sections were incubated for 10 min at room temperature with normal rabbit serum diluted at 1:10 in PBS and excess tapped off. Sheep anti-ERßcx sheep polyclonal antibody (1:800 dilution) in PBS was then applied to sections incubated overnight at 4°C. Negative controls consisted of the substitution of the primary antibody with PBS and with preabsorbed antibody. Sections were subsequently rinsed in PBS three times for 5 min before addition of the secondary antibody. Biotinylated antisheep antibody (1:200 dilution) in PBS was applied for 60 min at room temperature and subsequently washed off with PBS. Slides were then incubated with Vectastain ABC Regent (Vector Lab) for 1 h at room temperature and then washed in PBS. Color was developed with diaminobenzidine tetrahydrochloride. Sections were counterstained, dehydrated through graduated alcohol to xylene, and mounted with pertex. Evaluation of immunohistochemistry was carried out according to the methods published by Harvey et al. (29)
and Leake et al. (30)
. Briefly, this involves using a simple, additive scoring system based on the proportion and intensity of staining, resulting in a score of 0–8. Any scores >2 were considered positive. This is the same method of evaluation and cutoff score used by Saji et al. (28)
in their evaluation of ERßcx staining. Staining for ER was performed using the mouse monoclonal ER (F-10; Santa Cruz Biotechnology) antibody as described before.
Western Blotting.
For Western blotting, proteins were size fractionated by SDS-PAGE and transferred to polyvinylidene difluoride membranes. Membranes were incubated in blocking buffer (PBS containing 10% skimmed milk with 0.1% NP40) at room temperature, then incubated overnight at 4°C with either a sheep polyclonal anti-ERßcx antibody (diluted 1:1,000) in blocking buffer (28)
or the NH2-terminal ERß antibody described (diluted 1:500). Bound antibodies were detected using a horseradish peroxidase-conjugated donkey antisheep antibody and goat-antirabbit antibody (diluted 1:10,000; both from Dako). Antibody staining was detected using the enhanced chemiluminescence visualization system (ECL; Amersham Pharmacia Biotech) according to the manufacturer’s instructions. All of the immunoblots were strained with Ponceau (Sigma) after electroblotting to ensure even-transfer and protein integrity. The "nuclear" protein integrity was additionally confirmed by staining with two pan-ERß antibodies, which recognize the majority of all known ERß isoforms (data not shown). Every set of samples was electrophoresed with 5 ng of recombinant ERßcx and ERß1 (see Fig. 2A
controls) as an expression level/exposure standard. Western blots were simply scored positive or negative based on the presence of the appropriate sized band for ERßcx. The data from Western blotting and immunohistochemical staining were then assessed to see if a correlation existed between these two methods.
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tests for categorical variables (where applicable, Fisher’s exact tests were used) and both t and Mann-Whitney tests for continuous data. Kaplan-Meier plots were used to compare survival (death due to breast cancer) and relapse between the two groups with respect to ERßcx status, and differences were assessed using log rank tests. Estimates of relative survival were obtained using Cox proportional hazards models. Stata 7 program was used for all of the statistical analyses.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In total, 37 (45%) were positive and 45 (55%) negative for ERßcx. Of the benign samples, 25% were ERßcx positive and 75% were ERßcx negative. For the malignant breast cancers, 48% were ERßcx positive and 52% ERßcx negative. Fig. 1
shows representative Western blots for ERßcx.
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Association between ERßcx Status and Histopathological Features.
An analysis of whether any of the clinical or histopathological characteristics of the studied patients were associated with ERßcx status was conducted. This revealed no statistically significant associations between ERßcx and any of the clinicopathological features of the breast tumors. These results are summarized in Table 1
.
Analysis of ERßcx Status, and Time to Progression and Death.
To determine whether ERßcx status was predictive of time to disease progression or cancer death, the clinical notes of all of the women were reviewed to assess whether they had relapsed and/or died, and the time of these events from the initial diagnosis of breast cancer was recorded in months.
There were 15 relapses in the ERßcx-positive and 21 relapses in the ERßcx-negative group. Fig. 3
shows the Kaplan-Meier survival curves for relapse by ERßcx status. There was no statistically significant difference in relapse between the two groups {log rank test for equality of survivor functions x2 = 2.32; P = 0.13 hazard ratio of 0.60 [95% confidence interval (CI), 0.31–1.17] from Cox regression}. Seven patients in the ERßcx-positive and 13 in the ERßcx-negative group died because of breast cancer. There was a statistically significant difference in survival between the two groups (log rank test for equality of survivor functions, x2 = 3.86; P = 0.05; hazard ratio, 0.41; 95% CI, 0.16–1.03), and the Kaplan-Meier plot is shown in Fig. 3
.
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status with time to relapse and death. There were 23 relapses in the ER-positive and 12 relapses in the ER-negative group. There was no statistically significant difference in time to relapse between the two groups (log rank test for equality of survivor functions, x2 = 0.13; P = 0.72 hazard ratio of 0.88; 95% CI, 0.44–1.78) from Cox regression. There were 11 deaths in the ER-positive and 9 in the ER-negative group. There was again no statistically significant difference in death between the two groups (log rank test for equality of survivor functions x2 = 1.59; P = 0.21 hazard ratio of 0.57; 95% CI, 0.24–1.38) from Cox regression.
After adjusting for ER status, the hazard ratio for ERßcx in relation to time to relapse changed slightly to 0.62 (95% CI, 0.31–1.21). In adjusting for ER, there was a decrease from 73 to 69 in the number of patients with complete data. After adjusting for ER, the hazard ratio for ERßcx in relation to death remained the same at 0.41 (95% CI, 0.16–1.03), despite a slight reduction in the number of cases with complete records from 73 to 69. In conclusion, these data suggested that ER status alone or in association with ERßcx status does not offer better prediction of time to relapse or death than ERßcx status on its own.
Association between ERßcx Status and Response to Endocrine Treatment.
The records of all patients were reviewed, and patients who had received either neoadjuvant or palliative endocrine therapy and who had measurable disease were identified. The response to endocrine therapy was assessed according to the Response Evaluation Criteria in Solid Tumors guidelines (27)
. In a total of 23 patients identified, 12 ERßcx were positive and 11ERßcx negative. Of the 12 ERßcx-positive tumors, 6 had a complete or partial response, 5 had no change, and 1 had progressive disease, whereas among the 11 ERßcx negative patients, 4 had a complete or partial response, 1 had no change, and 6 had progressive disease (Table 2)
. Statistical analysis revealed that there was a statistically significant association between the ERßcx expression within breast tumors and the response to endocrine therapy (Fisher’s exact test, P = 0.04). The response to endocrine therapy was also reanalyzed based on ER status (Table 2)
. The result showed that there was no evidence of a statistically significant association between ER and response to endocrine therapy (Fisher’s exact test, P = 0.16). However, due to the small sample size concerning response to endocrine therapy and the fact that the majority of the samples were ER positive (20 of 23; 87%), it was not possible to assess whether the association between ERßcx and response to endocrine therapy was confounded by ER status.
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DISCUSSION |
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, and yet does not bind estradiol, suggesting a dominant-negative effect on ER function (20
, 31)
. These results led us to hypothesize that ERßcx expression in breast cancer could modulate the response to antiestrogens in cells coexpressing ER, and, thus, influence clinical outcome.
In the current study we have demonstrated that ERßcx protein is expressed in 48% of breast cancer samples and 25% of the benign samples by Western blotting with a specific antibody to ERßcx. We also validated the expression of ERßcx using immunohistochemistry in a number of cases and showed that the immunohistochemical analysis generally correlated with the Western blot results. Statistical analysis revealed that there was no significant associations between the expression of ERßcx and any of the clinicopathological features. We then examined the relationship between ERßcx status, and the time to progression and death from breast cancer in this group of women. With reference to the time to progression there was no statistical difference based on the ERßcx status of the breast tumors. However, when survival was investigated there was evidence of a statistically significant relationship between ERßcx status and survival, with ERßcx-positive patients having a survival advantage, hazard ratio of 0.41, and 95% CI, 0.16–1.03. These results, whereas significant, should be interpreted cautiously due to the relative small number of cases. An additional analysis should be undertaking adjusting for other prognostic/histopathological features. Because ER status has been shown previously to be useful for predicting overall patient survival as well as response to endocrine therapy in breast cancer, we also compared the ability of ERßcx and ER status in predicting relapse, patient survival, and response to endocrine therapy. Our result showed that ER status does not offer better prediction of time to relapse and survival than ERßcx status. There was also no evidence of an interaction between ERßcx and ER for either death (likelihood ratio test, P = 0.66) or time to relapse (likelihood ratio test, P = 0.16). When the response to endocrine therapy was reanalyzed based on ER status, the result again showed no evidence of a statistically significant association between ER and response to endocrine therapy (Fisher’s exact test, P = 0.16). However, we were unable to test whether the association between ERßcx and response to endocrine therapy was confounded by ER status, because the majority of the samples were ER positive (20 of 23; 87%). The high percentage of ER-positive samples probably reflects the rationale behind endocrine therapy, because antiestrogens are the treatment strategy adopted for ER-positive patients.
This is the first investigation to assess the relationship of ERßcx status to response to endocrine therapy, time to progression, and death in breast cancer using frozen clinical samples. Omoto et al. (32) have shown previously by reverse transcription-PCR analysis that ERßcx and ERß5 mRNAs are more highly expressed than ERß1 transcripts, with ERßcx mRNA expression significantly higher in breast cancers than normal tissue. In this particular study, immunohistochemical staining of clinical samples was also carried out using three different ERß antibodies and one ERßcx antibody. The authors detected an association of ERß expression with low histopathological grade breast cancer, but did not perform any correlation analysis between ERßcx positivity and any clinicopathological factors. The difference between the present study, which found an association between survival and the presence of ERßcx, and that of Omoto et al. (32) could be due to a number of factors. Primarily, the COOH-terminal region of ERß was assessed differently in the two studies. Our current study used an ERßcx COOH terminal-specific antibody, whereas the negative sample group in the study of Omoto et al. (32) could also consist of samples with an alternatively truncated ERß COOH terminus or other COOH-terminal variants not recognized by their ERß1. Furthermore, in the study by Omato et al. (32) , a sample was taken to be ERßcx positive if 25% of nuclei were stained positive, potentially allowing for a great deal of heterogeneity within the positively scored epithelial group, and possibly a majority of the sample could be negative as a whole and yet the sample classified as positive. Finally, the follow up in the current study was more than twice as long as that by Omoto et al. (32) , and this longer follow up would be more likely to reveal any effects of ERßcx on clinical outcome, if one existed.
Some clinical correlations with ERßcx expression have been observed previously. In a microarray analysis of 82 normal and malignant breast samples a cluster of 20 tumors with reduced expression of ERßcx was observed (33 , 34) . This group of tumors was found to have a high number of node-positive breast cancers, as well as distant metastasis at the time of diagnosis, and was at increased risk of developing metastatic disease (33 , 34) . In addition, Saji et al. (28) , in the correlation of pathological characteristics of the breast cancers with ERßcx, found that vascular invasion correlated significantly with a ERßcx-negative phenotype. The studies of Ahr et al. (33 , 34) and Saji et al. (28) also highlighted the fact that the loss of ERßcx may be associated with a phenotype that is generally: (a) more aggressive; (b) more likely to invade vasculature; (c) has a higher number of lymph nodes involved; (d) is more likely to have distant metastasis at the time of diagnosis; and (e) has an increased risk of developing metastatic disease. These reports generally support the notion that high levels of ERßcx expression correlate with better prognosis.
Results from the current study showed that the presence of ERßcx correlates with favorable response to endocrine therapy. In the ERßcx-positive tumors, 6 of 12 (50%) had either a partial or complete response to endocrine therapy, compared with 4 of 11 (36%) who were ERßcx negative. With regard to progressive disease, 1 of 12 (8%) in the ERßcx-positive group developed progressive disease, whereas on endocrine therapy, this compared with 6 of 11 (55%) who were ERßcx negative. This represents a statistically significant association between the presence of ERßcx and response to endocrine therapy (Fisher’s exact test, P = 0.04). When patients were included in the analysis who had a stabilization of their disease and could, therefore, be interpreted as to have derived clinical benefit from endocrine therapy, there were 11 of 12 (92%) in the ERßcx-positive group and 5 of 11 (45%) in the ERßcx negative group. This finding of ERßcx being associated significantly with response to endocrine therapy is in contrast to the result of Saji et al. (28) . There are a number of potential reasons for the discrepancy. Firstly, the populations studied and the techniques used differed. In this study the population had locally advanced or metastatic disease, and ERßcx expression was determined using Western blotting, whereas the population in the study by Saji et al. (28) was newly diagnosed and treated neoadjuvantly, and immunohistochemistry was used to measure ERßcx. Secondly, Western blotting was used to assess the ERßcx status in the frozen breast tissue in the current study, whereas Saji et al. (28) used immunohistochemistry. However, our Western blot data were also validated by parallel immunohistochemical analysis. It should also be noted that in both Saji et al. (28) and the current study, the number of patients assessed was small (18 and 23, respectively). Nevertheless, the current study has a longer follow-up, and the results are statistical significant.
There is still considerable controversy concerning the significance and function of ERßcx in breast cancer. Whereas this study has shown evidence of a direct and significant link between the expression of ERßcx and the response to endocrine therapy, the mechanism for this role is not clear. The dependence of tumors on estrogen, and, hence, their suitability for endocrine therapy, is known to be associated with the expression of functional ER. The rationale behind endocrine therapy for breast cancer is that ER-positive breast tumors depend on estrogen for growth and survival. As a result, ER antagonists, such as tamoxifen and faslodex, or aromatase inhibitors (compounds that inhibit local synthesis of estrogens from circulating C19 steroids) were used to disrupt the estrogen-dependent signaling (35)
. Given that ERßcx can have a dominant-negative effect on estrogen-dependent signaling through forming inactive heterodimers with ER (19
, 20
, 24)
, it is, therefore, possible that the expression of ERßcx could block estrogen-dependent signaling via ER and potentially synergize with antiestrogens, such as tamoxifen, thus making endocrine therapy more effective. If this hypothesis is correct, expression of ERßcx could be beneficial for the prognosis of breast cancer patients. Nevertheless, the modulation of ER-dependent estrogen signaling by ERßcx and ERß, and, thus, the success of endocrine therapy, would appear to be more complicated than first thought, and may involve a complex interplay between different ERß variants and ER in the epithelium, as well as in the stroma. To investigate in greater detail and to define accurately and definitively the role and predictive value of ERßcx, a larger immunohistochemical study with greater power using archival paraffin material from patients who have been treated and followed up for a long period of time is currently underway.
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FOOTNOTES |
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Requests for reprints: R. Charles Coombes, Department of Cancer Medicine, Cancer Cell Biology Group, Cancer Research United Kingdom Laboratories, 6th Floor MRC Cyclotron Building, Faculty of Medicine, Imperial College-London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, United Kingdom. E-mail: c.coombes{at}imperial.ac.uk
Received 9/12/03; revised 12/11/03; accepted 12/23/03.
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