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Advances in Brief |
-positive Breast Cancer
Department of Surgery, Breast Oncology Unit [S. S., M. T.] and Department of Pathology [Y. H., S-i. Ho.], Tokyo Metropolitan Komagome Hospital, 113-8677 Tokyo, Japan; Division of Endocrinology, Saitama Cancer Center Research Institute, 362-0806 Saitama, Japan [Y. O., S-i. Ha.]; Department of Medical Oncology, National Cancer Center Hospital, 104-0045 Tokyo, Japan [C. S., T. W.]; and Department of Medical Nutrition, Karolinska Institute, Huddinge, S141-86 Sweden [M. W., J-Å. G.]
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ABSTRACT |
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function. In this study we investigated the possibility that because the progesterone receptor (PR) gene is a downstream target of activated ER, in ER-positive breast cancers, expression of ERßcx would result in repression of PR. In ER-positive MCF-7 cells, stable transfection of an ERßcx expression vector resulted in reduced expression of PR without affecting ER expression. In breast cancers, immunohistochemical evaluation of ER-positive foci for the expression of PR and ERßcx revealed a significant correlation between a PR-negative phenotype and the presence of ERßcx within the foci. However, when entire lesions were evaluated by Allred scoring in 115 ER-positive breast cancer specimens, the presence of two distinct groups of patients could be discerned. One group expressed ERßcx and had very reduced levels of PR expression, as expected. The second group showed both ERßcx and high levels of PR. To evaluate the role of ERßcx in sensitivity to tamoxifen, 18 core needle biopsies, obtained before preoperative treatment with tamoxifen, were investigated. The results show that expression of ERßcx in primary lesions correlated with a poor response to tamoxifen, especially in cancers with a low PR expression in Allred score. This is the first evidence that evaluation of ERßcx along with PR may contribute to a better characterization of ER-positive breast cancers. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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3
and PR are still the most reliable markers for choosing treatment with antiestrogens, but about 30% of ER-positive metastasizing cancers do not respond to tamoxifen (2, 3, 4)
. The ability to identify this group of nonresponders would be of benefit to both the clinician and the patient.
The second ER, ERß, was reported in 1996 (5)
, so its presence was never considered when patient response to tamoxifen was evaluated. ERß is similar to ER with approximately 96% and 60% homology in the DNA-binding domains and ligand-binding domains, respectively. The tissue distribution and physiological functions of ERß and ER are different (5
, 6)
, and it is thought that ERß may also have distinct functions in the biology of breast cancer. Several variant forms of ERß have been reported to date. Among them is ERßcx, a splice variant that utilizes an alternative exon 8. This change in the COOH terminus results in very poor binding to E2, but ERßcx is capable of heterodimerization with ER and has a dominant negative effect on ER function (7
, 8)
. Because the PR gene is one of the representative downstream targets of ligand-activated ER (6)
, it seems likely that coexpression of ERßcx and ER could affect the expression of PR in breast cancer tissues, and this could be one of the conditions that would lead to ER-positive and PR-negative tumors.
With a specific antibody directed against exon 8 of ERßcx, we performed a detailed analysis of the expression of ER, PR, and ERßcx in breast cancer.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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MCF-7 cells were transfected with ERßcx expression vector with TransIT LT-1 reagent (Takara, Otsu, Japan). After 1 day in culture, the cells were grown in fresh RPMI 1640 supplemented with 10% FCS containing 1 mg/ml G418 for 10 days. Isolated colonies were trypsinized in metal ring cups, and the cells were further cultured in the presence of 200 µg/ml G418.
Immunoblotting.
Western blot analysis was performed as described previously (9)
. Briefly, aliquots of 100 µg of cell extract, which was taken from cells stimulated with E2, were subjected to SDS-PAGE in 10% acrylamide gels, and proteins were transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, MA). Blots were probed with primary anti-ER mouse polyclonal antibody (C-311; Santa Cruz Biotechnology, Santa Cruz, CA), anti-ERß rabbit polyclonal antibody (Upstate Biotechnology, Lake Placid, NY), anti-PR mouse monoclonal antibody (633; Dako, Kyoto, Japan), and anti-ERß rabbit polyclonal antibody (H-300; Santa Cruz Biotechnology). The secondary antimouse or antirabbit antibodies (Bio-Rad Laboratories, Hercules, CA) were conjugated with alkaline phosphatase. Detection was performed using Immun-Star Substrate (Bio-Rad Laboratories) and a Fuji Luminoimage Analyzer LAS-1000 system (Fuji Film, Tokyo, Japan).
Breast Cancer Samples.
Human breast cancer samples were obtained from patients undergoing partial or total mastectomy in Tokyo Metropolitan Komagome Hospital with the informed consent about the usage of resected tumors for research purposes. The ER content of samples resected during 1999–2000 was routinely evaluated by immunohistochemistry according to the following protocol.
Samples with neoadjuvant tamoxifen treatment were obtained as follows. Before the start of drug administration, core needle biopsies were taken from patients who entered the clinical trial for preoperative tamoxifen treatment. All patients were treated with 20 mg of tamoxifen daily for 3 months and subsequently had surgery. Histological factors were evaluated by pathologists at the National Cancer Center Hospital (Tokyo, Japan). The response of the primary tumors to tamoxifen was evaluated according to criteria established by the Japanese Breast Cancer Society, which are essentially the same as those established by the WHO. Complete response is defined as the disappearance of tumor, partial response refers to a decrease in tumor size of 
50%, NC indicates a decrease in tumor size of <50% or an increase of tumor size by <25%; PD indicates an increase in tumor size of 25%.
Immunohistochemistry.
The formaldehyde-fixed, paraffin-embedded samples were sequentially cut into 4-µm sections for staining. Antigens were retrieved by boiling the sections in 5% urea buffer for 20 min. The primary antibodies used were 1D5 for ER, PgR636 for PR (Dako), and ERß 14C8 (GeneTex, San Antonio, TX) for both the wt and cx forms of ERß. The amino acid sequence of the peptide used to raise the ERßcx-specific antibody was CMKMETLLPEATME. The peptide was coupled to keyhole limpet hemocyanin by the cysteine at the NH2 terminus to ensure a much better chance of obtaining a strong immune response. Preimmune serum taken from the sheep before immunization was used as a negative control for the antibody. Samples in which ERßcx mRNA was detected by RT-PCR (data not shown; Refs. 10
and 11
) were used as positive controls (Fig. 2, A and B)
. Tumors in which ERßcx mRNA was not detectable by RT-PCR (data not shown) were used as negative controls for the staining (Fig. 2C)
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, and Fig. 3
)].
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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would lead to inactivation of ER, and this would result in lower expression of PR. To determine whether expression of ERßcx affects the expression of PR in ER-positive human breast cancer cells, we established two clones of MCF-7 cells (MCF-7/ßcx-1 and MCF-7/ßcx-2) by stable transfection of the ERßcx-expressing vector. Expression of ERßcx in these transfected cells was monitored by Western blotting with an antibody that recognizes the NH2-terminal portion of ERß. This is a region present in both wt ERß and ERßcx. There was increased intensity of the ERß bands on Western blotting in transfected cells (Fig. 1)
. Because it is not possible to have wt ERß synthesized from ERßcx expression vector, the increase in the NH2-terminal signal indicates an increase in ERßcx.
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. In detail, PR-A was obviously reduced, but PR-B seemed to be slightly up-regulated.
Expression of ERßcx Correlates with PR-negative Phenotype in ER-rich Cancer Foci.
To determine whether the findings detected in cell clones hold true in clinical breast cancer, we proceeded to analyze the tissues obtained from breast cancer surgery.
First, for analysis of the expression of ERßcx protein on paraffin-embedded specimens, we developed a specific ERßcx antibody that was raised against the unique COOH-terminal sequence of ERßcx as described in "Materials and Methods." In samples in which ERßcx mRNA was confirmed to be present by RT-PCR (data not shown; Ref. 10
), this antibody detected nuclear localized signals with slight cytoplasmic staining (Fig. 2A)
. No such signals were seen with preimmune serum (Fig. 2B)
. In samples that had no ERßcx mRNA, there was cytoplasmic but not nuclear staining (Fig. 2C)
. Commercially available mouse monoclonal ERß antibody, 14C8, which should bind both wt ERß and ERßcx, showed intense nuclear signals (Fig. 2D)
on the same samples used in Fig. 2, A and B
. ERßcx antibody also detected nuclear signals with slight cytoplasmic staining on the same area of a sequentially cut slide (Fig. 2E)
. From these findings, the nuclear staining with the ERßcx antibody was considered positive for ERßcx.
A total of 115 individual human breast cancer samples, consecutively obtained during 1999–2000, were evaluated as ER positive by routine immunohistochemical analysis with standard criteria (10% of total cells were positive). Of these, 54 specimens were chosen for the initial experiment because these sections each had an ER-rich focus (a single independent component consisting of about 500-2000 cancer cells in which ER was expressed in >80% of the cells as shown in Fig. 2, F and I
). Staining and evaluation of these selected foci made it possible to see whether the expression of ERßcx correlates with lack of PR in an almost homogenous ER-positive group of cells.
Three sequential slides were stained with ER, ERßcx, and PR antibodies. Fig. 2, I–K
, shows representative cases of ERßcx-negative tumors. In the areas that were ER rich (Fig. 2I)
with only cytoplasmic ERßcx staining (Fig. 2J)
, almost all cells were PR positive (Fig. 2K)
. However, in fields where there is ER (Fig. 2F)
and nuclear ERßcx staining (Fig. 2G)
, there is no evidence of PR (Fig. 2H)
. A summary of the 54 fields examined is shown in Table 1
. Not all cases were homogeneously stained with ERßcx and PR antibody as seen in the sample illustrated in Fig. 2, F–K
. For this reason and to analyze the data statistically, arbitrary cutoff limits were used. For PR, 10% of positivity was used as the cutoff value. With ERßcx, only the cases with >60% positive staining were categorized as "positive" in Table 1
. With these criteria, 14 of 54 foci examined were evaluated as positive for ERßcx.
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Relationship between ERßcx and PR in ER-positive Breast Cancer Tissues; Evaluation of Entire Specimens.
The results seemed to indicate that the presence of ERßcx in a tumor would be synonymous with ER-positive and PR-negative breast cancer. However, this relationship was detected only in limited parts of breast cancer, where ER was abundantly expressed. As is widely known, human breast cancers are generally heterogeneous and are composed of many various cells. We therefore examined the expression of ERßcx in entire lesions in breast cancer specimens and analyzed these data with the clinical information of the patients. We used the Allred score, which is widely used for the evaluation of hormone responsiveness of clinical breast cancer (12)
.
In total, 115 breast cancer samples were stained with ER, ERßcx, and PR antibodies, and the proportion and intensity of staining on the entire lesion were scored by the Allred method. Sample results of ERßcx staining are shown in Fig. 2, L–N
. An evaluation was made as to whether any characteristics of the patient’s disease could be correlated with the presence or absence of ERßcx (Table 2)
. Venous invasion of cancer cells was significantly correlated with a ERßcx-negative phenotype, but there was no statistically significant correlation between expression of ERßcx and other factors including PR.
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. The dotted line on the graph indicates the cutoff value decided from the mean values of each receptor’s Allred scores. It is clear from the graph that there are two distinct groups of patients. One group expresses ERßcx and has very reduced levels of PR expression, and the other group expresses both ERßcx and high levels of PR.
Possible Significance of ERßcx in ER-positive Breast Cancer as a Predictive Factor of Tamoxifen Treatment.
From our results, the relationship between ERßcx and PR in clinical breast cancer is not as simple as was found in breast cancer cell lines. To understand the clinical meaning of the results depicted in Fig. 3A
, we acquired biopsies from patients who entered a clinical trial in which they were treated with tamoxifen as their primary therapy before surgery. These samples are rare because this type of treatment is not commonly applied. By evaluation of the response of the primary tumor to tamoxifen, these samples make it possible to evaluate whether the presence of ERßcx and PR affects the response to tamoxifen. Eighteen core needle biopsies from individual patients could be evaluated by immunohistochemistry for ER, ERßcx, and PR. All samples were rich in ER expression, as evaluated as 5–8 total points in Allred score. Fig. 3B
shows the distribution of ERßcx and PR scores. Open circles indicate NC or PD (i.e., patients whose primary tumor did not respond well to tamoxifen). The important findings from Fig. 3B
are as follows: (a) eight of nine patients (89%) lacking ERßcx responded well to tamoxifen, although in ERßcx-positive cases, only four of nine (44%) patients responded; and (b) none of the four patients who were ERßcx positive but PR poor showed any response to tamoxifen.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-positive cancers generally implies that ER is not active in vivo (4)
. This inactivity could be due to defects in the receptor itself or to the absence of estrogen. Because mutations or defects in ER are not common in human breast cancer (14)
, loss of PR is generally thought to be due to the lack of estrogen. Recent use of an aromatase inhibitor in postmenopausal patients showed that PR-positive cancers sometimes become PR negative after inhibition of aromatase (15)
. This result suggests that lack of ligands is one important source of the ER-positive/PR-negative phenotype, although this is not true in all cases.
MCF-7/ßcx-1 and MCF-7/ßcx-2, which are MCF-7 cells stably expressing ERßcx, showed reduced expression of PR (PR-A + PR-B) without any effect on the level of ER. These results, together with the findings in clinical samples shown in Table 1
and Fig. 1, F–H
, indicate that in addition to the availability of ligands, expression of ERßcx may be another source of the ER-positive/PR-negative phenotype in a cancer cell.
PR-A and PR-B are products of a single gene transcribed from different promoters. PR-B functions as a transcriptional activator on progesterone-responsive promoters, whereas PR-A acts as a repressor of the function of PR-B and ER (13)
. The consequences of the expression ratio of these PRs in breast cancer have not been defined in terms of their contribution to the malignant phenotype and to responsiveness to endocrine therapy (16)
. In ERßcx transformants, PR-A was dominantly inhibited, but PR-B seemed to be slightly up-regulated. The difference in regulation of PR-A and PR-B by introduction of ERßcx should be investigated in more detail in additional experiments, including an assessment of whether this effect is really through the interaction with ER or through the action of ERßcx on the promoter of the PR gene.
Mote et al. (17) reported that, with formalin-fixed samples, commonly used antibodies frequently failed to detect PR-B in immunohistochemical analysis. This is thought to be due to masking epitopes on PR-B protein. If this is the case, the loss of PR in our immunohistochemical studies must mean mainly loss of PR-A.
Predicting the response to tamoxifen in breast cancer patients is difficult for the clinician. Although this drug has been widely used as an adjuvant after breast cancer surgery, it is generally used along with chemotherapy (1) . Patients who are given tamoxifen alone are usually lower-risk patients and rarely relapse. It is therefore unusual to obtain appropriate samples from poor responders. We were fortunate to obtain core needle biopsies from tumors before treatment with preoperative tamoxifen. Clinical evaluation of primary tumor size after 3 months of treatment allowed us to find poor responders. Although the sample size is small, our analysis revealed that tumors that had ERßcx staining, especially with poor expression of PR, did not seem to be good candidates for tamoxifen treatment. As a supporting finding, we have observed that MCF-7/ßcx clones lost the ability to grow in response to estrogen, and tamoxifen could no longer inhibit growth (detailed data will appear elsewhere4 with molecular analysis).
In contrast to this type of ERßcx-positive tumor, we also found by evaluation with Allred score in 115 clinical samples that there are ERßcx-positive tumors that are also rich in PR. Because this group showed good response to tamoxifen in core needle analysis (four of five tumors responded), it is possible that the level and function of ER in these tumors are high enough to overcome the presence of ERßcx, although current experiments were not designed to test this. In addition to this, our initial hypothesis was that expression of ERßcx, if expressed at high levels and coexpressed in breast cancer cells with ER, can reduce PR levels in those cells. Therefore, the presence of ERßcx does not necessarily permit the conclusion that ER is repressed. If ER and ERßcx are not coexpressed, PR can still be expressed.
The opposite concern in the ERßcx-positive/PR-negative group is that the amount and distribution of ERßcx may not be sufficient to silence the widely distributed ER in some cases. Because the presence of ERßcx seemed to alter the ratio of PR-A:PR-B (Fig. 1)
, ERßcx may influence PR promoter usage. It is therefore valid to begin to think of ERßcx as a transcriptional regulator in its own right, independent of ER. If this is the case, ERßcx itself may alter the expression of PR, even when it is expressed at low levels. Of course, we cannot exclude the possibility that expression of ERßcx is more widespread than can be detected by present immunohistochemical methods.
As is often experienced, evidence obtained in cell culture studies does not fully reflect what happens in tissues. However, we believe that the results from our cell culture experiments offer an explanation for why patients whose tumors are ERßcx positive and PR negative do not respond to tamoxifen, whereas those with ERßcx-positive and PR-positive tumors do.
In this study we have presented the first evidence for the presence and pattern of expression of ERßcx protein in clinical ER-positive breast cancers. We have also found that expression of ERßcx influences PR expression. This information may be useful for identifying patients who will respond to tamoxifen treatment. Further analysis in collaboration with large clinical institutes, which can provide samples in the neoadjuvant setting, will be required to define the clinical significance of our findings.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Princess Takamatsu Cancer Research Fund (Grant 00-23205), the Sagawa Cancer Research Fund, the Swedish Cancer Society, and KaroBio AB. 
2 To whom requests for reprints should be addressed, at Department of Surgery, Breast Oncology Unit, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, 113-8677 Tokyo, Japan. Fax: 81-3-3824-1552; E-mail: ss-saji{at}wa2.so-net.ne.jp
3 The abbreviations used are: ER, estrogen receptor; PR, progesterone receptor; E2, estradiol; RT-PCR, reverse transcription-PCR; NC, no change; PD, progressive disease; PS, proportion score; IS, intensity score; wt, wild-type; CMV, cytomegalovirus.
4 Y. Omoto, et al., manuscript in preparation..
Received 5/15/02. Accepted 7/12/02.
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