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Clinical Cancer Research Vol. 11, 3170-3174, May 1, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Increased Estrogen Receptor ßcx Expression during Mammary Carcinogenesis

Majida Esslimani-Sahla1,2, Andrew Kramar3, Joelle Simony-Lafontaine2, Margaret Warner4, Jan-Åke Gustafsson4 and Henri Rochefort1

Authors' Affiliations: 1 Endocrinologie moléculaire et cellulaire des cancers (U540), Institut National de la Santé et de la Recherche Médicale; Departments of 2 Pathology and 3 Biostatistics, Cancer Center Val d'Aurelle, Montpellier, France; and 4 Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge, Sweden

Requests for reprints: Henri Rochefort, Endocrinologie moléculaire et cellulaire des cancers (U540), Institut National de la Sante et de la Recherche Medicale, 60 rue de Navacelles, 34090 Montpellier, France. Phone: 33-467043760; Fax: 33-467540598; E-mail: henri.rochefort{at}montp.inserm.fr.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Identification of proteins that markedly vary during early steps of mammary carcinogenesis may help to understand its pathophysiology and to develop a prevention strategy. The expression of total estrogen receptor ß (ERß) protein and of its COOH-terminally spliced variant ERßcx (or ERß2) was compared in 43 invasive breast cancers and in 39 adjacent normal mammary glands and 26 ductal carcinoma in situ (DCIS). Thirty-six breast cancers were ER positive by radioligand binding assay. The analysis was done by immunohistochemistry on adjacent sections of formalin-fixed, paraffin-embedded tumors using polyclonal anti-ERß 503 IgY and sheep polyclonal ERßcx antibodies that were previously validated. Nuclear staining was quantified using a computerized image analyzer in selected areas of normal and cancer epithelial cells. Total ERß expression was high in normal glands, decreased in DCIS (P = 0.0004), and increased from DCIS to invasive tumors (P = 0.029). In contrast, the ERßcx expression was low in normal glands, increased significantly in DCIS (P = 0.0014), and continued to increase in invasive carcinomas (P = 0.0027) in both ER{alpha}-positive and ER{alpha}-negative tumors. This is the first study showing a significant increase of the ERßcx variant protein in DCIS and invasive breast cancer compared with adjacent normal glands. This contrasts with the decrease of the total ERß level in the same patients and indicates different mechanisms to explain these variations during mammary carcinogenesis. It also suggests a role of the ERßcx variant in carcinogenesis opposite to the protective effect of the wild-type ERß1.

Key Words: Estrogen receptor ß • splicing • normal glands • breast cancer • ductal carcinoma in situ • immunohistochemistry • carcinogenesis

The pathophysiology of sporadic human breast cancer remains poorly understood, although the facilitating role of ovarian hormones seems to be critical (1). The multistep model of carcinogenesis established for colorectal cancer (2) might also be valid in understanding mammary carcinogenesis based on the increased risk of proliferative lesions and of in situ carcinoma as defined by Dupont and Page (3). One approach to understand the first steps of human mammary carcinogenesis is to compare the expression of putative oncogenes and tumor suppressor genes in normal glands, high-risk benign breast disease, and in in situ carcinoma. In addition to early genetic alterations (4), the analysis of protein expression by immunohistochemistry could be decisive. Among the proteins involved in sporadic human breast cancers, those related to estrogen action are good candidates; estrogens are known to be tumor promoters via their mitogenic activity (1). The balance between the levels of the two estrogen receptors, ER{alpha} and ERß (5), their spliced variants (6), and of nuclear receptor coregulators may be important in modulating the mammary tumor promoter effect of estrogens. ERß is not required for ductal development in mammary gland (7) but it inhibits the activity of ER{alpha} after heterodimerization (8, 9). Whereas the level of ER{alpha} begins to increase in proliferative mammary gland with atypia (10, 11), the expression of total ERß begins to decrease in proliferative benign breast disease without atypia to become the lowest in ductal carcinoma in situ (DCIS; ref. 12). The two receptors are differently spliced leading to several variants. The significance of ER{alpha} variants in carcinogenesis is not clear but few studies were made at the protein level (reviewed in ref. 13). Two spliced variants of ERß1 (ERß2 or ERßcx) and ERß5 mRNA are expressed in breast cancer (14, 15). ERßcx also expressed as a protein (15, 16) does not bind estrogens but inhibits both ER{alpha} and ERß transcriptional activity by heterodimerization (17).

Using polyclonal antibodies specific to the human ERßcx and to the total amount of ERß (18), which have been validated previously (12, 18, 19), we have compared by computer-aided immunohistochemistry the expression levels of these proteins in epithelial cells of invasive breast carcinoma, DCIS, and normal mammary glands located in the same section.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patient population. Forty-three primary breast carcinomas, removed by surgery in 1992 at the Montpellier Cancer Center, were selected from the archival files because they contained normal ducts and/or lobules and/or DCIS at the periphery of the tumor. Thirty-six invasive breast cancers were ER-positive by radioligand binding assay and were previously studied (19). Seven additional tumors were chosen as ER negative by immunohistochemistry (ER{alpha} antibody, clone 6F11, Novocastra, Newcastle, United Kingdom) and radioligand assay.

The median age of patients was 62 years; 77% were postmenopausal as determined by clinical and hormonal analysis. Ninety-one percent of invasive breast cancers were ductal and 9% were lobular. According to a modified Scarff-Bloom-Richardson grading system (19), 19% of tumors were of grade 1, 36% grade 2, and 45% grade 3. Tumor size status was pT1 (44%), pT2 (49%), and pT3/pT4 (2%). Histologic node invasion was in 51% of cases. The median ER cytosolic level, by radioligand assay, was 59 fmol/mg protein (range 0-441), with seven cases with ER < 10 fmol/mg protein. The median progesterone receptor cytosolic level was 55 fmol/mg protein (range 0-576). Ten DCIS structures were of low nuclear grade, 12 of intermediate grade, and 4 of high grade.

Immunohistochemistry. Immunohistochemistry was done using chicken polyclonal ERß 503 IgY antibodies, which recognize total ERß proteins (both full-length ERß and its splice variants), and with the sheep polyclonal ERßcx antibody, raised against the 14 amino acids peptide of the COOH-terminal region: MKMETLLPEATMEQ (from the laboratory of J-A. Gustafsson).

Immunohistochemical study was done on alcohol–formalin-fixed paraffin-embedded sections as described (12, 19). Briefly, the avidin-biotin-peroxidase complex method was applied after a heat-induced antigen retrieval by pressure cooking in EDTA buffer (pH 7) for 15 minutes. 3,3'-Diaminobenzidine was used as chromogen. ERßcx specificity of immunostaining was shown previously (19) by preincubating the ERßcx antibody with a 10-fold excess of ERßcx peptide and with preadsorbed ERßcx antiserum. The immunostaining specificity with ERß 503 IgY antibodies was shown previously by protein extinction (12, 19). In each experiment, a negative control was done with IgY antibodies from nonimmunized serum (Nordic, Tilburg, the Netherlands) and with preimmune sheep serum for ERßcx. Positive external controls were used in sections of OVCAR cells embedded in paraffin pellet for ERß and in a breast cancer paraffin block expressing ERßcx.

HER-2/neu protein level was estimated using polyclonal A0485 (DAKO) and monoclonal CB11 (Novocastra) antibodies, with the automated DAKO Autostainer according to the manufacturer's instructions and the DAKO Hercept Test scoring.

Quantitative method. Quantification was done using a computerized image analyzer (Samba 2005 TITN Alcatel, Grenoble, France; refs. 12, 19). This is an objective automatic method of quantification, guided by the pathologist who selected fields containing only epithelial cells (normal or pathologic), with a program quantifying only nuclear staining. Staining of stromal and inflammatory cells was not quantified. Serial, stained slides were analyzed for ERß and ERßcx. Representative fields of invasive carcinoma and adjacent components of normal and DCIS were analyzed. Results were expressed as the percentage of nuclear-stained epithelial cells and as a quantitative immunocytochemical (QIC) score [= (percentage of surface stained in epithelial cells) x1 (mean staining intensity) x 10]. The percentage of nuclear staining of negative control, which was usually nil or weak, was subtracted.

Statistical analysis. Quantitative ERß and ERßcx expressions for pooled comparisons of the three structures were done with the Kruskal-Wallis nonparametric test. The Wilcoxon sign rank test was used for comparisons between paired samples, containing the same components at the periphery of tumor. P values <5% were considered statistically significant.


   Results
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 Materials and Methods
 Results
Discussion
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ERßcx staining distribution. ERßcx expression varied between the patients and from normal tissue to breast cancer in the same patients. Intense and diffuse ERßcx nuclear immunostaining (in brown) was seen in invasive carcinomatous cells (Fig. 1). It contrasted with the weak staining of a few luminal and basal epithelial cells of normal mammary ducts (Fig. 1A and B) or lobules (Fig. 1C). The ERßcx expression in in situ carcinomas was variable, but generally intermediate between normal and invasive carcinoma as shown in two examples (Fig. 1D-F). ERßcx immunoreactivity was also seen in some stromal cells, lymphocytes, and macrophages (Fig. 1). However, these cells were not selected and, therefore, not quantified by the image analyzer. A weak or moderate cytoplasmic staining was considered as nonspecific because, contrary to nuclear staining, it was not eliminated by adding the peptide or using preadsorbed serum (12, 19).



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  		Fig. 1. Differential expression of the ERßcx protein. Nuclear positive ERßcx staining (brown) was significantly higher in invasive breast cancer (red arrows) than normal duct (*; A and B) or normal lobule (*; C) where nuclei were mostly blue. In DCIS (blue arrows), the nuclear ERßcx expression was either clearly lower (D) than in adjacent invasive breast cancer (D, inset) or only slightly lower (F) than in adjacent invasive breast cancer (E) as shown in two typical examples. DCIS staining was, however, always higher (D and F) than in normal glands (A-C). ERßcx was also expressed in some stromal and inflammatory cells (black arrows). Magnification, x200 (A, D, E, F); x400 (B-C). ERßcx staining specificity was shown previously (19).

 
Comparison of total ERß and ERßcx expression levels between normal glands, ductal carcinoma in situ, and invasive carcinomas. When comparing pools of normal tissue and lesions (Fig. 2A; Table 1A), the total ERß level (percentage of stained nuclei) decreased significantly from normal glands to DCIS (P < 0.0001), confirming our data from another series (12). Total ERß level also decreased, but to a lower extent, from normal glands to invasive breast cancer (P = 0.002) because it increased from DCIS to invasive breast cancer (P = 0.042). The ERß variant responsible for this increase was not defined. ERßcx level evaluated in adjacent serial sections was found to vary in opposite direction from normal gland to DCIS than total ERß (Fig. 2B; Table 1A). ERßcx increased gradually from normal glands to DCIS (P < 0.0001) as well as to invasive breast cancer (P < 0.0001). ERßcx levels increased to a lower extent from DCIS to invasive breast cancer.



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  		Fig. 2. Comparison of ERß (A) and ERßcx (B) levels in adjacent sections between three structures: invasive breast cancer, peripheral normal glands, and/or DCIS. Expression levels were estimated by immunohistochemistry and a computer-aided image analyzer. n = number of each pooled structures. The median value of each pooled structure is represented by a bar ({04-2298fx03l}). The different structures in the same tumor section are connected for ER-positive tumors: (- - -, {triangleup}) and for ER-negative tumors: (—, {bullet}). The HER-2/neu–positive tumors are indicated by arrows. The P values, determined by the Wilcoxon rank test, indicate the statistical difference between paired structures.

 

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  		Table 1. Comparison of ERß and ERßcx levels in adjacent normal glands (N), ductal carcinomas in situ (DCIS) and invasive breast carcinomas (IBC) in pools of each component (A) and in paired cases (B)

 
When comparing the pairs of two different structures in the same tumor sections, as shown in Fig. 2 and summarized in Table 1B, the dissociated evolution of ERß and ERßcx levels from normal to in situ carcinoma and invasive breast cancer were also significantly different.

Similar variations were observed by using the QIC score, which include the staining intensity of nuclei with a significant increase of ERßcx expression from normal glands to invasive breast cancer for the whole population, confirming examples of Fig. 1.

Interestingly, the increase of ERßcx expression was also observed in five of seven ER{alpha}-negative invasive breast cancer, suggesting that it was independent of estrogens binding to ER{alpha}.

Only three cases of invasive breast cancer, which were ER negative by immunohistochemistry and radioligand binding assay (Fig. 2) and their adjacent high nuclear grade DCIS overexpressed HER-2/neu protein. The ERßcx level in invasive breast cancer was independent of HER-2/neu or ER{alpha}-positive status but two ER{alpha}-negative and one HER-2/neu positive invasive breast cancer strongly expressed ERßcx (Fig. 2B). In a previous study (19), we showed that expression of ERß and ERßcx in breast cancer was not correlated to any classic parameters; the only correlation found was between ERß and ERßcx at the stage of invasive breast cancer.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this pilot study, we confirm on another series of samples that the expression of total ERß protein significantly decreases from normal glands to DCIS (12). However, total ERß slightly increases from DCIS to invasive cancer. This contrasts with another study (20), suggesting that total ERß expression decreased in invasive carcinomas but not in DCIS. The reason for this difference is unknown, as well as the nature of the variant that is responsible for the increase in our study. The major new information of our study concerns the evolution of the ERßcx variant that is generally low in normal glands but highly variable in cancer cells with a significant and progressive increase in DCIS and in invasive breast cancer. The dissociated evolution of ERß and its spliced form, ERß2, indicates different mechanisms dysregulating the expression of these variants in carcinoma cells and suggests different significance of the two ERß variants in carcinogenesis.

There are few studies of ERßcx in breast cancer and the significance of its expression is not clear because ERßcx has been shown to have both good (21) and bad (15) prognostic significance. Studies comparing ERßcx in normal mammary glands and invasive breast cancer were mostly done at the RNA level. The increased expression of ERßcx in breast cancer was proposed to be due to inflammatory cells infiltrating the tumor (14). A study showed an increase in the expression of ERßcx protein in invasive breast cancer (54%) compared with a pool of normal tissue (only 9% positive; ref. 15). Our study confirms this finding by comparing the two types of tissue in the same tumor sections and by quantifying only epithelial and cancer cell expression, excluding interference from inflammatory cells and fibroblasts. Furthermore, we show that the increased ERßcx protein expression is already observed in DCIS, suggesting that it may be an early and critical event in mammary carcinogenesis. A similar increase of the ERßcx variant was observed in prostate cancer (22). The function of the two forms of ERß in breast cancer may be different. Following separate transfection of their cDNA into MCF7 cells, the genes regulated by ERß2 or ERß1 are different (23). The association of the decreased expression of ERß with the increased expression of ERßcx and ER{alpha} might lead to an increased sensitivity of transformed mammary cells to estrogen, allowing them to be growth stimulated after menopause by lower estrogen concentrations. It is, therefore, tempting to speculate that the increase of ERßcx, associated with a decrease of ERß, facilitates mammary carcinogenesis. Increased splicing variants have been described in several cancers (24), including mammary tumors (25). It is frequent that alternative splicing inactivates the wild-type tumor suppressor genes in carcinogenesis (24) and ERß has been proposed to behave as a tumor suppressor by inhibiting the estrogen mitogenic activity (8, 12, 26). Even if the increased ERßcx/ERß1 ratio has not yet been proven to facilitate carcinogenesis, it might be very useful as a marker to detect high-risk lesions and facilitate early diagnosis of transformation. The mechanism responsible for the modification of ERß splicing in carcinogenesis is unknown, but might be specific because the {Delta}5-6–deleted ERß variant RNA was specifically decreased in breast cancer compared with normal glands (27). Further studies are required to specify the possible involvement of SR proteins (28), splicing site mutations, or nuclear receptor comodulators controlling transcription and splicing (29). Moreover, differential methylation of the ERß1, but not the ERßcx promoter gene, might explain the selective decreased ERß1 level during tumorigenesis (20, 30).

To conclude, this pilot retrospective study points to a differential dysregulation of ERß1 and ERßcx in in situ mammary carcinoma. The intriguing evolution of this ERß1/ERß2 ratio during early steps of mammary carcinogenesis will require more extensive and prospective studies to elucidate several questions concerning its mechanism and significance in the pathophysiology, early detection, and monitoring of breast cancer.


   Acknowledgments
 
We thank Drs. Philippe Rouanet, Bernard Saint-Aubert, Jean Grenier, Frederic Bibeau, François Quenet, and G. Romieu (CRLC Val d'Aurelle, Montpellier, France) for supplying clinical data; Jean-Yves Cance for the skillful preparation of the figures; and Roselyne Lavaill for her excellent technical help.


   Footnotes
 
Grant support: Institut National de la Sante et de la Recherche Medicale, Ligue Nationale Contre le Cancer, and Académie Nationale de Médecine (M. Esslimani-Sahla); and grants from Swedish Cancer Society and KaroBio AB (J-A. Gustafsson).

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.

Received 11/10/04; revised 2/ 3/05; accepted 2/ 4/05.


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