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Endocrinology |
Laboratoire de Biologie Cellulaire et Hormonale, Hôpital Arnaud-de-Villeneuve, 34059 Montpellier Cédex, France [H. R.]; Laboratoire d’Anatomie et Cytologie Pathologiques, Hôpital Lapeyronie, 34059 Montpellier Cédex, France [P. R., P. B.]; Endocrinologie Moléculaire et Cellulaire des Cancers (U 540) INSERM, 34090 Montpellier, France [P. R., M. E. S., H. R.]; and Department of Biosciences and Medical Nutrition, Karolinska Institute, Novum, Huddinge University Hospital, S-141 86 Huddinge, Sweden [S. M., J. A. G.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and Ki67 immunostaining. The percentage of ERß-positive cells was high (median, 85%) in "normal" mammary glands and in nonproliferative BBD and decreased significantly (P < 0.0001) in proliferative BBD without atypia and in CIS, contrasting with an inverse progression for the ER level. In normal mammary glands, the ERß level did not vary according to the nature of the lesion at the periphery and was significantly higher (P < 0.007) than in adjacent preinvasive lesions, except in nonproliferative BBD. The ERß level decreased in proliferative BBD, anticipating the ER increase, which was significant in BBD with atypia. In high-grade ductal carcinoma in situ, both ER levels were low. The ratio between ERß and ER was high in normal glands, and decreased significantly in proliferative lesions. ERß staining was inversely correlated with Ki67 (r = -0.333; P < 0.001), more particularly in high-grade ductal carcinoma in situ (r = -0.57; P < 0.02). The marked and early decreased level of ERß protein associated with other criteria of cell proliferation suggests a protective effect of ERß against the mitogenic activity of estrogens in mammary premalignant lesions. Knowledge of the ERß and ER content in each preinvasive lesion should help to rationalize antiestrogen preventive therapy adapted to each individual patient. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, but not of ERß, seems to be required to develop mammary duct and breast cancer, as shown by knock-out experiments in mice (8
, 9)
. In vitro functional studies suggest that ERß might modulate ER action (10
, 11)
. However, the first results, based mostly on the estimation of ERß mRNA by reverse transcription-PCR analysis, have been controversial because ERß has been suggested to be of both good (12
, 13)
and bad (14)
prognostic significance in breast cancer.
The development of antibodies specific to human ER (15)
and more recently to ERß (16)
allows study of the expression of these two genes at the protein level in an attempt to understand their significance in mammary carcinogenesis and, possibly, to use them to help define adequate targeted preventive therapies. We previously showed in a population of preinvasive mammary lesions significantly increased ER expression in BBD with atypia and in low-grade CIS with no correlation with cathepsin D expression (17)
.
In the same population of patients, we have now quantified the expression of ERß in the nuclei of epithelial and cancer cells at five different stages as described by Dupont and Page (2)
according to the risk of developing invasive breast cancer. The results were compared with ER and Ki67 expression to determine whether the ERß level varied in preinvasive lesions and how it varied compared with ER.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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were included in a multicenter prospective study from 1994 to 1998 at the University Hospitals of Montpellier and Nîmes, France. Written consent was obtained for all patients. Investigations were approved by the local ethics committee. In 61 patients, blood samples were collected for hormone assay on the day of surgery, and hormonal status was defined as described (17)
. Among the 55 menopausal patients, 11 received estrogen replacement therapy.
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. BBDs were classified according to the relative risk of invasive breast cancer using the criteria of Dupont and Page (2)
and DCIS according to the nuclear grade (18
, 19) . For each patient, formalin-fixed, paraffin-embedded tissue blocks containing the highest risk lesion and histologically normal glandular structures at the periphery of lesions were selected. When different histological lesions with the same risk were present, they were included, which explains why 130 lesions were analyzed in only 118 patients. Low- and intermediate-grade DCIS and LCIS samples were pooled for statistical analysis. One high-grade DCIS was associated with LCIS. A total of 3 atypical hyperplasias and 37 CISs were located at the periphery of invasive carcinomas. No significant difference was found for ERß staining in these lesions compared with CIS and atypical hyperplasia without invasive carcinoma, allowing these lesions to be included in the study.
Immunohistochemistry.
ERß immunohistochemical analysis was performed on each paraffin-embedded block (5-µm section) and on an adjacent section stained previously with the 1D5 ER monoclonal antibodies (17
, 20)
, using the chicken polyclonal ERß503 IgY antibody (16)
. This antibody recognizes total ERß proteins. Immunostaining was revealed by a streptavidin-biotin enhanced immunoperoxidase technique. After antigen retrieval by pressure cooking in 0.1 M EDTA buffer (pH 7.2) for 10 min (21)
and endogenous peroxidase blocking with 1% H202, sections were incubated with normal donkey serum (1:40 dilution) in PBS for 30 min at 22°C. Sections were then incubated overnight at 4°C with ERß 503 IgY (1:1250 dilution). The complex was revealed using antichicken biotinylated antibody (1:300 dilution; Vector, Compiègne, France) and streptavidin-peroxidase complex (1:1000 dilution; Dako, Trappes, France). 3,3'-Diaminobenzidine tetrahydrochloride (Sigma, Saint Quentin Fallavier, France) was used as chromogen, and the samples were counterstained with hematoxylin (Dako), dehydrated, and mounted. Tissue sections were washed with 0.1% Tween 20 in PBS between each immunostaining step. Immunostaining specificity was checked by preincubating ERß 503 IgY with a 90-fold excess of recombinant human ERß (Panvera, Madison, WI) or with nonspecific IgY (1:36000 dilution; Nordic, Tilburg, the Netherlands). In each experiment, sections of rat prostate and paraffin-embedded cell pellets (ERß-positive cancer cell line) were used as positive external controls. Ki67 staining was performed using the MIB1 antibody (Immunotech, Marseilles, France) on 61 lesions (22)
. We used the same antigen retrieval procedure that was used for ERß. Immunostaining was revealed using a streptavidin-biotin immunoperoxidase technique.
Immunostaining Quantification.
ERß and Ki67 staining was quantified on structures corresponding to higher risk lesions and in adjacent histologically normal ducts and lobules with an image analyzer as described for ER (17)
. Only nuclei were quantified following nuclear counterstaining and automatic selection by the analyzer. ERß staining was expressed as a percentage of positive nuclei.
Statistical Analysis.
To compare the ERß and ER values between all groups, we used the Kruskal-Wallis test. When the test was significant, we used the Bonferroni correction to look for significance of subgroups. For paired samples, we used the Wilcoxon test for two samples. The correlation between the former variables was estimated using the Spearman test. The overall threshold of significance was 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, shows the specificity of ERß immunostaining using the 503 IgY antibody. This antibody gives strong immunoreactivity in the nuclei of epithelial cells and weak cytoplasmic staining. Nuclear staining was completely eliminated when the antibodies were preadsorbed with ERß protein, whereas cytoplasmic staining persisted, suggesting a cross-reactivity with other cytoplasmic proteins. In this study, only nuclear staining in epithelial or tumoral cells was quantified. Interestingly, ERß, but not ER, was also present in the nuclei of cells other than epithelial cells, in both "normal" and tumoral structures, particularly in fibroblasts, lymphocyte infiltrates (6)
, macrophages, and in the endothelial cells of vessels (Fig. 1, e and f)
, as has also been described in rodents (16
, 23)
. In the normal resting gland, ERß was present both in luminal and myoepithelial cells (Fig. 1e)
, whereas ER was detected only in some luminal epithelial cells (Fig. 1d)
. In most lesions, there was no parallelism between ER and ERß staining, as shown in Fig. 1, d, e, g, and h
, which illustrate the case of a single patient. This dissociation also confirmed the absence of cross-reactivities between the two antibodies to ER and to ERß, as has been established in other studies (16
, 24)
and in cells transfected with only ER or ERß.4
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was found to vary according to patient, but was much higher in normal mammary glands and in nonproliferative BBD and decreased significantly (P < 0.0001) in proliferative BBD without atypia and in CIS. Fig. 1
shows representative strong ERß staining in a normal duct (Fig. 1e)
and cyst (Fig. 1f)
and its decrease in high-risk lesions such as proliferative BBD (Fig. 1i)
and DCIS (Fig. 1h)
. Fig. 3
illustrates the ERß level in each lesion with the corresponding normal adjacent glands. In normal mammary glands, the percentage of ERß-positive cells was high and did not vary according to the nature of the lesion at the periphery, contrary to ER-positive cells in the adjacent section (17)
. The ERß level significantly decreased (P < 0.007) in all preinvasive lesions except in nonproliferative BBD compared with adjacent normal glands.
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Levels.
illustrates the dissociation between ER (Fig. 1, d and g)
and ERß (Fig. 1, e and h)
staining in a representative normal duct and in an intermediate-grade DCIS. The ER level was studied previously on adjacent sections of ERß (17)
, and the distribution of ERß and of ER nuclear staining was compared in normal mammary glands (at the periphery of the lesions) and in the five groups with increasing risk for invasive breast cancer (Fig. 4)
. In normal glands and in nonproliferative BBD, ER levels were low (respective median values, 4 and 1.3%), whereas ERß levels were high (respective median values, 85 and 79%). ERß decreased in proliferative BBD, anticipating the ER increase described previously (17)
in proliferative BBD with atypia. In high-grade DCIS, both ERs were generally low or absent. Fig. 5
shows the ratio of the ERß level (+ 1) to the ER level (+ 1) in normal glands and in the preinvasive lesions. This ratio was high (>10) in normal glands and in nonproliferative BBD and then decreased as the risk of invasive cancer increased.
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. Ki67 staining was negatively correlated with ERß in both lesions and normal glands (r = -0.33; P < 0.001). The negative correlation was stronger when only the proliferative ducts with atypia and DCIS (r = -0.46; P < 0.01) or high-grade DCIS (r = -0.57; P < 0.02) were considered. No correlation was obtained between Ki67 and ER staining (not shown).
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No significant difference in ERß level attributable to menopausal and hormonal status was observed on this limited number of informed patients, contrasting with the ER regulation observed in our study on 151 patients (17)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß) during early stages of mammary carcinogenesis were studied by immunohistochemistry in epithelial mammary structures of increasing risk of developing invasive breast cancer, from simple BBD without cell proliferation to high-grade CIS. The percentage of ER-positive cells is generally considered to be low (10–20%) in normal resting mammary glands (16
, 17
, 25
, 26)
and to increase in proliferative BBD (26)
, particularly when associated with atypia (17)
, and in low-grade DCIS. This increase has suggested an increased receptivity to estrogens in these tissues, contributing to their increased risk of tumorigenesis (27)
.
In this study, we show a marked decrease of ERß-positive cells, statistically significant in the stage of proliferative breast disease without atypia and anticipating the ER increase observed in BBDs with atypia. The ERß level was further decreased in DCIS, mostly in high-nuclear-grade DCIS (median value, 3%). In proliferative BBD with atypia, there was additional increased ER expression (17)
, resulting in a large decrease in the ERß/ER ratio. Therefore, in the histologically normal resting mammary gland, ERß-positive cells (median, 85%) greatly exceed ER-positive cells (median, 4%), whereas the ER level progressively reached the ERß level in BBD with atypia and in CIS. Ki67 staining, a marker of cell proliferation and, to a lesser extent, cathepsin D staining, was inversely correlated with the ERß level.
Concerning mammary tumorigenesis, the decreased ERß protein level that we observed in human preinvasive mammary lesions is in line with the decreased ERß RNA level in invasive breast cancer tissues compared with the adjacent normal mammary gland (12)
and with studies on mice mammary glands using the same antibodies (16)
. These results also support the hypothesis that ERß might generally inhibit the mitogenic activity of estrogens mediated by ER, as proposed from ERß gene knock-out experiments showing increased Ki67 staining and signs of hyperplasia in mouse endometrium and prostate (9
, 23
, 24)
and from ERß RNA assays in other human estrogen-responsive cancers (28
, 29)
.
The mechanism of the putative effect of ERß on cell proliferation is unknown. Functional studies in cancer cell lines have shown differences in stimulating the transcriptional activating function (AF1) of the receptor (10)
and activator protein (AP1) cross talk (11)
; however, the master genes involved in the mitogenic activity of estrogens are still being debated. Moreover, the ERß expressed in stromal and vascular cells close to premalignant epithelial cells might also play a paracrine role in controlling cell proliferation (30)
. This study shows in preinvasive lesions a correlation between a decreased ERß level and increased risk of breast cancer associated with these lesions. This decrease, as well as the increased Ki67 staining, might help to detect lesions with increasing risk. Long-term clinical follow-up of these patients could clarify this issue. Because the 503 IgY antibodies do not discriminate between the different ERß isoforms (31
, 32)
, it is possible that the proportion of these forms also modulates ER function differently in mammary tumorigenesis. The mechanism of the ERß down-regulation is probably to be sought within epithelial mammary cells because the level of ERß in normal mammary glands (contrasting with that of ER) was not altered by the varying level in the adjacent lesions.
We conclude that the expression of ERß markedly decreases in the early stages of mammary carcinogenesis. The mechanism and role of this decrease in carcinogenesis are unknown. However, these results are consistent with a preventive effect of ERß against the mitogenic effect of estrogens in human premalignant lesions and in line with the results of ßERKO and ERKO in mice, indicating a stimulatory role of ER and an inhibitory effect of ERß in the proliferation of different estrogen-responsive tissues. Better knowledge of the ER and ERß content in each preinvasive lesion should help in the future to rationalize the use of preventive therapy with antiestrogen (33)
adapted to each individual patient.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Centre Hospitalier Universitaire of Montpellier, a grant from the French Ministry of Health (to H. R.), the Fondation pour la Recherche Médicale (to P. R.), the Swedish Cancer Fund (to J. A. G.), and the Institut National de la Santé et de la Recherche Médicale. 
2 To whom requests for reprints should be addressed, at Endocrinologie Moléculaire et Cellulaire des Cancers, (U 540) INSERM, 60 rue de Navacelles, 34090 Montpellier, France. Phone: (33) 4 67 04 37 61; Fax: (33) 4 67 54 05 98; E-mail: henri.rochefort{at}montp.inserm.fr
3 The abbreviations used are: CIS, carcinoma in situ; BBD, benign breast disease; ER, estrogen receptor; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ.
4 M. Warner, S. Mäkelä, S. Nilsson, and J-Å. Gustafsson, unpublished experiments.
Received 10/ 4/00. Accepted 1/16/01.
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M. Esslimani-Sahla, J. Simony-Lafontaine, A. Kramar, R. Lavaill, C. Mollevi, M. Warner, J.-A. Gustafsson, and H. Rochefort Estrogen Receptor {beta} (ER{beta}) Level but Not Its ER{beta}cx Variant Helps to Predict Tamoxifen Resistance in Breast Cancer Clin. Cancer Res., September 1, 2004; 10(17): 5769 - 5776. [Abstract] [Full Text] [PDF]
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A. Bardin, P. Hoffmann, N. Boulle, D. Katsaros, F. Vignon, P. Pujol, and G. Lazennec Involvement of Estrogen Receptor {beta} in Ovarian Carcinogenesis Cancer Res., August 15, 2004; 64(16): 5861 - 5869. [Abstract] [Full Text] [PDF]
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C. Palmieri, E. W.-F. Lam, J. Mansi, C. MacDonald, S. Shousha, P. Madden, Y. Omoto, A. Sunters, M. Warner, J.-A. Gustafsson, et al. The Expression of ER{beta}cx in Human Breast Cancer and the Relationship to Endocrine Therapy and Survival Clin. Cancer Res., April 1, 2004; 10(7): 2421 - 2428. [Abstract] [Full Text] [PDF]
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S. Paruthiyil, H. Parmar, V. Kerekatte, G. R. Cunha, G. L. Firestone, and D. C. Leitman Estrogen Receptor {beta} Inhibits Human Breast Cancer Cell Proliferation and Tumor Formation by Causing a G2 Cell Cycle Arrest Cancer Res., January 1, 2004; 64(1): 423 - 428. [Abstract] [Full Text] [PDF]
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 O. M. Tirado, D. M. Selva, N. Toran, C. A. Suarez-Quian, M. Jansen, D. P. McDonnell, J. Reventos, and F. Munell Increased Expression of Estrogen Receptor {beta} in Pachytene Spermatocytes After Short-Term Methoxyacetic Acid Administration J Androl, January 1, 2004; 25(1): 84 - 94. [Abstract] [Full Text] [PDF]
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V. Pais, I. Leav, K.-M. Lau, Z. Jiang, and S.-M. Ho Estrogen Receptor-{beta} Expression in Human Testicular Germ Cell Tumors Clin. Cancer Res., October 1, 2003; 9(12): 4475 - 4482. [Abstract] [Full Text] [PDF]
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 J. Matthews and J.-A. Gustafsson Estrogen Signaling: A Subtle Balance Between ER{alpha} and ER{beta} Mol. Interv., August 1, 2003; 3(5): 281 - 292. [Abstract] [Full Text] [PDF]
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 M. Marino, F. Acconcia, and A. Trentalance Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells Mol. Biol. Cell, June 1, 2003; 14(6): 2583 - 2591. [Abstract] [Full Text] [PDF]
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E. Tan-Chiu, J. Wang, J. P. Costantino, S. Paik, C. Butch, D. L. Wickerham, B. Fisher, and N. Wolmark Effects of Tamoxifen on Benign Breast Disease in Women at High Risk for Breast Cancer J Natl Cancer Inst, February 19, 2003; 95(4): 302 - 307. [Abstract] [Full Text] [PDF]
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H. Buteau-Lozano, M. Ancelin, B. Lardeux, J. Milanini, and M. Perrot-Applanat Transcriptional Regulation of Vascular Endothelial Growth Factor by Estradiol and Tamoxifen in Breast Cancer Cells: A Complex Interplay between Estrogen Receptors {alpha} and {beta} Cancer Res., September 1, 2002; 62(17): 4977 - 4984. [Abstract] [Full Text] [PDF]
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 M.-M. Liu, C. Albanese, C. M. Anderson, K. Hilty, P. Webb, R. M. Uht, R. H. Price Jr., R. G. Pestell, and P. J. Kushner Opposing Action of Estrogen Receptors alpha and beta on Cyclin D1 Gene Expression J. Biol. Chem., June 28, 2002; 277(27): 24353 - 24360. [Abstract] [Full Text] [PDF]
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 V Speirs, G P Skliris, S E Burdall, and P J Carder Distinct expression patterns of ER{alpha} and ER{beta} in normal human mammary gland J. Clin. Pathol., May 1, 2002; 55(5): 371 - 374. [Abstract] [Full Text] [PDF]
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G. J. Pepe, R. B. Billiar, M. G. Leavitt, N. C. Zachos, J. A. Gustafsson, and E. D. Albrecht Expression of Estrogen Receptors {alpha} and {beta} in the Baboon Fetal Ovary Biol Reprod, April 1, 2002; 66(4): 1054 - 1060. [Abstract] [Full Text] [PDF]
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 B. A. Stoll Oestrogen/insulin-like growth factor-I receptor interaction in early breast cancer: clinical implications Ann. Onc., February 20, 2002; 13(2): 191 - 196. [Abstract] [Full Text] [PDF]
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G. Lazennec, D. Bresson, A. Lucas, C. Chauveau, and F. Vignon ER{beta} Inhibits Proliferation and Invasion of Breast Cancer Cells Endocrinology, September 1, 2001; 142(9): 4120 - 4130. [Abstract] [Full Text] [PDF]
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 S. Signoretti and M. Loda Estrogen Receptor {beta} in Prostate Cancer : Brake Pedal or Accelerator? Am. J. Pathol., July 1, 2001; 159(1): 13 - 16. [Full Text] [PDF]
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