Summary
Estrogen receptor (ER) α is a well-established independent prognostic factor in breast cancer whose presence determines the clinical implications of adjuvant endocrine therapy. A second receptor, ERb has been described, and a number of studies have examined its expression in breast tissue. However elucidation of the role played by ERb has been hampered by published immunohistochemical studies employing a variety of protocols and scoring systems such that inter-laboratory comparisons are difficult. Here we present a multi-centre study designed to critically evaluate inter-laboratory differences in methodology. Six UK and Irish centres participated in this study. A small series of breast cancers were stained using centre-specific laboratory protocols and scored using both centrespecific and standard scoring protocols. There was generally poor agreement as to what constituted a positive or negative case when centre-specific scoring systems were used with less than half of all cases in agreement. Concordance was improved when a standard scoring system was used but varied according to threshold for positivity employed and primary antibody. Our results emphasise the need for further studies addressing the role of ERb to be based on a wider consensus on criteria for positivity. Ideally this should be based on calibration against clinical outcome.
Similar content being viewed by others
References
GGJM Kuiper E Enmark M Pelto-Huikko S Nilsson J-A Gustafsson (1996) ArticleTitleCloning of a novel estrogen receptor expressed in rat prostate and ovary Proc Natl Acad Sci USA 93 5925–5930 Occurrence Handle10.1073/pnas.93.12.5925 Occurrence Handle8650195
S Mosselman J Polman R Dijkema (1996) ArticleTitleER-β: identification and characterisation of a novel human estrogen receptor FEBS Lett 392 49–53 Occurrence Handle10.1016/0014-5793(96)00782-X Occurrence Handle8769313
GB Tremblay A Tremblay NG Copeland DJ Gilbert NA Jenkins F Labrie V Giguere (1997) ArticleTitleCloning, chromosomal localization, and functional analysis of the murine estrogen receptor β Mol Endocrinol 11 353–365 Occurrence Handle10.1210/me.11.3.353 Occurrence Handle9058381
PT Saunders MR Millar K Williams S Macpherson D Harkiss RA Anderson B Orr NP Groome G Scobie HM Fraser (2000) ArticleTitleDifferential expression of estrogen receptor -α and -β and androgen receptor in the ovaries of marmosets and humans Biol Rep 63 1098–1105
V Speirs IP Adams DS Walton SL Atkin (2000) ArticleTitleIdentification of wild type and exon 5 deletion variants of estrogen receptor β in normal human mammary gland J Clin Endo Metab 85 1601–1605 Occurrence Handle10.1210/jc.85.4.1601
G Pelletier M El-Alfy (2000) ArticleTitleImmunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs J Clin Endocrinol Metab 85 4835–4840 Occurrence Handle10.1210/jc.85.12.4835 Occurrence Handle11134151
IP Braidman L Hainey G Batra PL Selby PT Saunders JA Hoyland (2001) ArticleTitleLocalisation of estrogen receptor beta protein expression in adult human bone J Bone Miner Res 16 214–220 Occurrence Handle11204421
I Leav KM Lau JY Adams JE McNeal ME Taplin J Wang H Singh SM Ho (2001) ArticleTitleComparative studies of the estrogen receptors β and α and the androgen receptor in normal prostate glands, dysplasia and in primary and metastatic carcinoma Am J Pathol 159 79–92 Occurrence Handle11438457
H Akgun J Lechago M Younes (2002) ArticleTitleEstrogen receptor-β is expressed in Barrett’s metaplasia and associated adenocarcinoma of the esophagus Anticancer Res 22 1459–1461 Occurrence Handle12168823
HO Critchley TA Henderson RW Kelly GS Scobie LR Evans NP Groome PT Saunders (2002) ArticleTitleWild-type estrogen receptor (ERβ1) and the splice variant (ERβcx/β2) are both expressed within the human endometrium throughout the normal menstrual cycle J Clin Endocrinol Metab 87 5265–5273 Occurrence Handle10.1210/jc.2002-020502 Occurrence Handle12414901
C Palmieri GJ Cheng S Saji M Zelada-Hedman A Warri Z Weihua S Van Noorden T Wahlstrom RC Coombes M Warner JA Gustafsson (2002) ArticleTitleEstrogen receptor beta in breast cancer Endocr Relat Cancer 9 1–13 Occurrence Handle10.1677/erc.0.0090001 Occurrence Handle11914179
PT Saunders MR Millar S Macpherson DS Irvine NP Groome LR Evans RM Sharpe GA Scobie (2002) ArticleTitleERβ1 and ERβ2 splice variant (ERβcx/β2) are expressed in distinct cell populations in the adult human testis J Clin Endocrinol Metab 87 2706–2715 Occurrence Handle10.1210/jc.87.6.2706 Occurrence Handle12050238
LP Stabile AL Davis CT Gubish TM Hopkins JD Luketich N Christie S Finkelstein JM Siegfried (2002) ArticleTitleHuman non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen Cancer Res 62 2141–2150 Occurrence Handle11929836
V Pais I Leav KM Lau Z Jiang SM Ho (2003) ArticleTitleEstrogen receptor-beta expression in human testicular germ cell tumors Clin Cancer Res 9 4475–4482 Occurrence Handle14555521
PA Konstantinopoulos A Kominea G Vandoros GP Sykiotis P Andricopoulos I Varakis G Sotiropoulou-Bonikou AG Papavassiliou (2003) ArticleTitleOestrogen receptor beta (ERβ) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation Eur J Cancer 39 1251–1258 Occurrence Handle10.1016/S0959-8049(03)00239-9 Occurrence Handle12763213
JM Harvey GM Clark CK Osborne DC Allred (1999) ArticleTitleEstrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer J Clin Oncol 17 1474–1481 Occurrence Handle10334533
EV Jensen G Cheng C Palmieri S Saji S Makela S Noorden ParticleVan T Wahlstrom M Warner RC Coombes JA Gustafsson (2001) ArticleTitleEstrogen receptors and proliferation markers in primary and recurrent breast cancer Proc Natl Acad Sci USA 98 15197–15202 Occurrence Handle10.1073/pnas.211556298 Occurrence Handle11734621
P Roger ME Sahla S Makela JA Gustafsson P Baldet H Rochefort (2001) ArticleTitleDecreased expression of estrogen receptor β protein in proliferative preinvasive mammary tumours Cancer Res 61 2537–2541 Occurrence Handle11289127
GP Skliris PJ Carder MR Lansdown V Speirs (2001) ArticleTitleImmunohistochemical detection of ERβ in breast cancer: towards more detailed receptor profiling Br J Cancer 84 1095–1098 Occurrence Handle10.1054/bjoc.2001.1721 Occurrence Handle11308260
V Speirs GP Skliris SE Burdall PJ Carder (2002) ArticleTitleDistinct expression patterns of ERα and ERβ in normal human mammary gland J Clin Path 55 371–374 Occurrence Handle11986344
PT Saunders MR Millar K Williams S Macpherson C Bayne C O’Sullivan TJ Anderson NP Groome WR Miller (2002) ArticleTitleExpression of oestrogen receptor β (ERβ1) protein in human breast cancer biopsies Br J Cancer 86 250–256 Occurrence Handle10.1038/sj.bjc.6600035 Occurrence Handle11870515
JA Shaw K Udokang JM Mosquera H Chauhan JL Jones RA Walker (2002) ArticleTitleOestrogen receptors α and β differ in normal human breast and breast carcinomas J Pathol 198 450–457 Occurrence Handle10.1002/path.1230 Occurrence Handle12434414
SA Fuqua R Schiff I Parra JT Moore SK Mohsin CK Osborne GM Clark DC Allred (2003) ArticleTitleEstrogen receptor β protein in human breast cancer: correlation with clinical tumour parameters Cancer Res 63 2343–2439
AM Shaaban PA O’Neill MPA Davies R Sibson CR West PH Smith CS Foster (2003) ArticleTitleDeclining estrogen receptor-β expression defines malignant progression of human breast neoplasia Am J Sug Pathol 27 1502–1512 Occurrence Handle10.1097/00000478-200312000-00002
V Speirs (2002) ArticleTitleOestrogen receptor β in breast cancer: good, bad or still too early to tell J Pathol 197 143–147 Occurrence Handle10.1002/path.1072 Occurrence Handle12015736
GP Skliris AT Parkes JL Limer SE Burdall PJ Carder V Speirs (2002) ArticleTitleEvaluation of seven oestrogen receptor β antibodies for immunohistochemistry, Western blotting and flow cytometry in human breast tissue J Pathol 197 155–162 Occurrence Handle10.1002/path.1077 Occurrence Handle12015738
V Speirs PJ Carder MRJ Lansdown (2002) ArticleTitleOestrogen receptor β: how should we measure this? Br J Cancer 87 687 Occurrence Handle10.1038/sj.bjc.6600534 Occurrence Handle12237781
PTK Saunders WR Miller (2002) ArticleTitleAuthor’s reply Reply Br J Cancer 87 688–689 Occurrence Handle10.1038/sj.bjc.6600535
GP Skliris K Munot SM Bell PJ Carder S Lane K Horgan MRJ Lansdown AT Parkes AM Hanby AF Markham V Speirs (2003) ArticleTitleReduced expression of oestrogen receptor β in invasive breast cancer and its re-expression using DNA methyltransferase inhibitors in a cell line model J Pathol 201 213–220 Occurrence Handle10.1002/path.1436 Occurrence Handle14517838
DC Allred JM Harvey M Berado GM Clark (1998) ArticleTitlePrognostic and predictive factors in breast cancer by immunohistochemical analysis Mod Pathol 11 155–168 Occurrence Handle9504686
P Balfe A McCann A McGoldrick K McAllister M Kennedy P Dervan MJ Kerin (2004) ArticleTitleEstrogen receptor α and β profiling in human breast cancer Eur J Surg Oncol 30 469–474 Occurrence Handle10.1016/j.ejso.2004.02.010 Occurrence Handle15135471
L Nakopolou AC Lazaris Panayotopoulou Givalos Giannopoulou N Markaki A Keramopoulos (2004) ArticleTitleThe favourable prognostic expression of oestrogen receptor β immunohistochemical expression in breast cancer J Clin Pathol 57 523–528 Occurrence Handle10.1136/jcp.2003.008599 Occurrence Handle15113861
DM Barnes RR Millis LVAM Beex SM Thorpe RE Leake (1998) ArticleTitleIncreased use of immunohistochemistry of oestrogen receptor measurement in mammary carcinoma: the need for quality assurance Eur J Cancer 34 1677–1682 Occurrence Handle10.1016/S0959-8049(98)00149-X Occurrence Handle9893651
S Ogawa S Inoue T Watanabe A Orimo T Hosoi Y Ouchi M Muramatsu (1998) ArticleTitleMolecular cloning and characterization of human estrogen receptor βcx: a potential inhibitor of estrogen action in human Nucleic Acids Res 26 3505–3512 Occurrence Handle10.1093/nar/26.15.3505 Occurrence Handle9671811
JT Moore DD McKee K Slentz-Kesler LB Moore SA Jones EL Horne JL Su SA Kliewer JM Lehmann TM Willson (1998) ArticleTitleCloning and characterization of human estrogen receptor β isoforms Biochem Biophys Res Commun. 247 75–78 Occurrence Handle10.1006/bbrc.1998.8738 Occurrence Handle9636657
I Poola (2003) ArticleTitleMolecular assays to profile 10 estrogen receptor beta isoform mRNA numbers in ovary, breast, uterus and bone tissues Endocrine 22 101–111 Occurrence Handle10.1385/ENDO:22:2:101 Occurrence Handle14665713
Y Miyoshi T Taguchi JA Gustafsson S Noguchi (2001) ArticleTitleClinicopathological characteristics of estrogen receptor-beta-positive breast cancers Jpn J Cancer Res 92 1057–1061 Occurrence Handle11676856
I Poola R Clarke R DeWitty LD Lefall (2002) ArticleTitleFunctionally active estrogen receptor isoform profiles in the breast tumors of African American women are different from the profiles in breast tumors of Caucasian women Cancer 94 615–623 Occurrence Handle10.1002/cncr.10274 Occurrence Handle11857292
R Leake D Barnes S Pinder I Ellis L Anderson T Anderson R Adamson T Rhodes K Miller R Walker (2000) ArticleTitleImmunohistochemical detection of steroid receptors in breast cancer: a working protocol J Clin Pathol 53 634–635 Occurrence Handle10.1136/jcp.53.8.634 Occurrence Handle11002770
Speirs V, Carder PJ, Lane S, Dodwell D, Lansdown MRJ, Hanby AM: Oestrogen receptor β: what it means for patients with breast cancer. Lancet Oncol 5: 174–181, 2004 (Erratum in: Lancet Oncol 5: 208, 2004).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carder, P.J., Murphy, C.E., Dervan, P. et al. A Multi-Centre Investigation Towards Reaching a Consensus on the Immunohistochemical Detection of ERβ in Archival Formalin-fixed Paraffin Embedded Human Breast Tissue. Breast Cancer Res Treat 92, 287–293 (2005). https://doi.org/10.1007/s10549-004-4262-8
Issue Date:
DOI: https://doi.org/10.1007/s10549-004-4262-8