The Role of Estrogen Receptor-β in Breast Cancer

Abstract

The discovery of a second estrogen receptor (ER), ERβ, has led to a reevaluation of estrogen action. The widespread expression of ERβ-like proteins in normal and neoplastic mammary tissues suggests a role of ERβ in the breast. Little progress has been made in elucidating this role or roles, but the presence of two ERs and variant isoforms in breast cancers presents challenges and opportunities to tease out complexities in understanding the estrogen signaling pathway in breast tissues. Identification of two groups of ERβ-expressing tumors in vivo, and the possibility of differential function, has already raised expectations that targeting ERβ may offer new treatment options for breast cancer patients where previously only aggressive chemotherapies were available. This supports continued efforts to understand the nature and function of ERβ in breast cancer, but it also suggests that ER status may need to be redefined to include an assessment of ERβ isoforms in addition to ERα.

Keywords

estrogen receptor-β - isoforms - breast cancer - biomarker - endocrine therapy - resistance

• References

• 1 Speirs V, Skliris G, Burdall S, Carder P. Distinct expression patterns of ERa and ERb in normal human mammary gland. J Clin Pathol 2002; 255: 371-374
• 2 Clarke RB, Howell A, Potten CS, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 1997; 57 (22) 4987-4991
• 3 Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us?. Endocr Rev 1999; 20 (3) 358-417
• 4 Förster C, Mäkela S, Wärri A , et al. Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci U S A 2002; 99 (24) 15578-15583
• 5 Antal MC, Krust A, Chambon P, Mark M. Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERbeta-null mutant. Proc Natl Acad Sci U S A 2008; 105 (7) 2433-2438
• 6 Nilsson S, Mäkelä S, Treuter E , et al. Mechanisms of estrogen action. Physiol Rev 2001; 81 (4) 1535-1565
• 7 Dotzlaw H, Leygue E, Watson PH, Murphy LC. Expression of estrogen receptor-beta in human breast tumors. J Clin Endocrinol Metab 1997; 82 (7) 2371-2374
• 8 Enmark E, Pelto-Huikko M, Grandien K , et al. Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82 (12) 4258-4265
• 9 Fuqua SA, Schiff R, Parra I , et al. Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer. Cancer Res 1999; 59 (21) 5425-5428
• 10 Järvinen TA, Pelto-Huikko M, Holli K, Isola J. Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol 2000; 156 (1) 29-35
• 11 Fox EM, Davis RJ, Shupnik MA. ERbeta in breast cancer—onlooker, passive player, or active protector?. Steroids 2008; 73 (11) 1039-1051
• 12 Skliris GP, Leygue E, Curtis-Snell L, Watson PH, Murphy LC. Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J Cancer 2006; 95 (5) 616-626
• 13 Monroe DG, Secreto FJ, Subramaniam M, Getz BJ, Khosla S, Spelsberg TC. Estrogen receptor alpha and beta heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells. Mol Endocrinol 2005; 19 (6) 1555-1568
• 14 Weitsman GE, Skliris G, Ung K , et al. Assessment of multiple different estrogen receptor-beta antibodies for their ability to immunoprecipitate under chromatin immunoprecipitation conditions. Breast Cancer Res Treat 2006; 100 (1) 23-31
• 15 Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer?. Endocr Relat Cancer 2006; 13 (2) 327-334
• 16 Chi A, Chen X, Chirala M, Younes M. Differential expression of estrogen receptor beta isoforms in human breast cancer tissue. Anticancer Res 2003; 23 (1A) 211-216
• 17 Saji S, Omoto Y, Shimizu C , et al. Expression of estrogen receptor (ER) (beta)cx protein in ER(alpha)-positive breast cancer: specific correlation with progesterone receptor. Cancer Res 2002; 62 (17) 4849-4853
• 18 Shaaban AM, Green AR, Karthik S , et al. Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 2008; 14 (16) 5228-5235
• 19 Yan M, Rayoo M, Takano EA, Fox SB ; kConFab Investigators. Nuclear and cytoplasmic expressions of ERβ1 and ERβ2 are predictive of response to therapy and alters prognosis in familial breast cancers. Breast Cancer Res Treat 2011; 126 (2) 395-405
• 20 Moore JT, McKee DD, Slentz-Kesler K , et al. Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 1998; 247 (1) 75-78
• 21 Savinov AY, Remacle AG, Golubkov VS , et al. Matrix metalloproteinase 26 proteolysis of the NH2-terminal domain of the estrogen receptor beta correlates with the survival of breast cancer patients. Cancer Res 2006; 66 (5) 2716-2724
• 22 Sanchez M, Picard N, Sauvé K, Tremblay A. Challenging estrogen receptor beta with phosphorylation. Trends Endocrinol Metab 2010; 21 (2) 104-110
• 23 Hamilton-Burke W, Coleman L, Cummings M , et al. Phosphorylation of estrogen receptor beta at serine 105 is associated with good prognosis in breast cancer. Am J Pathol 2010; 177 (3) 1079-1086
• 24 Roger P, Sahla ME, Mäkelä S, Gustafsson JA, Baldet P, Rochefort H. Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res 2001; 61 (6) 2537-2541
• 25 Rutherford T, Brown WD, Sapi E, Aschkenazi S, Muñoz A, Mor G. Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 2000; 96 (3) 417-421
• 26 Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW. Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 2000; 60 (2) 245-248
• 27 Leav I, Lau KM, Adams JY , et al. Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 2001; 159 (1) 79-92
• 28 Zhu X, Leav I, Leung YK , et al. Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 2004; 164 (6) 2003-2012
• 29 Al-Nakhle H, Burns PA, Cummings M , et al. Estrogen receptor beta1 expression is regulated by miR-92 in breast cancer. Cancer Res 2010; 70 (11) 4778-4784
• 30 Smith L, Brannan RA, Hanby AM , et al. Differential regulation of estrogen receptor beta isoforms by 5′ untranslated regions in cancer. J Cell Mol Med 2009; ; July 28 (Epub ahead of print)
• 31 Murphy LC, Peng B, Lewis A , et al. Inducible upregulation of oestrogen receptor-beta1 affects oestrogen and tamoxifen responsiveness in MCF7 human breast cancer cells. J Mol Endocrinol 2005; 34 (2) 553-566
• 32 Zhao C, Dahlman-Wright K, Gustafsson JA. Estrogen signaling via estrogen receptor beta. J Biol Chem 2010; 285 (51) 39575-39579
• 33 Chang EC, Frasor J, Komm B, Katzenellenbogen BS. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology 2006; 147 (10) 4831-4842
• 34 Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res 2004; 64 (1) 423-428
• 35 Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology 2001; 142 (9) 4120-4130
• 36 Tonetti DA, Rubenstein R, DeLeon M , et al. Stable transfection of an estrogen receptor beta cDNA isoform into MDA-MB-231 breast cancer cells. J Steroid Biochem Mol Biol 2003; 87 (1) 47-55
• 37 Hou YF, Yuan ST, Li HC , et al. ERbeta exerts multiple stimulative effects on human breast carcinoma cells. Oncogene 2004; 23 (34) 5799-5806
• 38 Warner M, Gustafsson JA. The role of estrogen receptor beta (ERbeta) in malignant diseases—a new potential target for antiproliferative drugs in prevention and treatment of cancer. Biochem Biophys Res Commun 2010; 396 (1) 63-66
• 39 Rousseau C, Nichol JN, Pettersson F, Couture MC, Miller Jr WH. ERbeta sensitizes breast cancer cells to retinoic acid: evidence of transcriptional crosstalk. Mol Cancer Res 2004; 2 (9) 523-531
• 40 Helguero LA, Faulds MH, Gustafsson JA, Haldosén LA. Estrogen receptors alfa (ERalpha) and beta (ERbeta) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 2005; 24 (44) 6605-6616
• 41 Cheng G, Weihua Z, Warner M, Gustafsson JA. Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland. Proc Natl Acad Sci U S A 2004; 101 (11) 3739-3746
• 42 Skliris GP, Lewis A, Emberley E , et al. Estrogen receptor-beta regulates psoriasin (S100A7) in human breast cancer. Breast Cancer Res Treat 2007; 104 (1) 75-85
• 43 O’Neill PA, Davies MP, Shaaban AM , et al. Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br J Cancer 2004; 91 (9) 1694-1702
• 44 Leung YK, Mak P, Hassan S, Ho SM. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci U S A 2006; 103 (35) 13162-13167
• 45 Peng B, Lu B, Leygue E, Murphy LC. Putative functional characteristics of human estrogen receptor-beta isoforms. J Mol Endocrinol 2003; 30 (1) 13-29
• 46 Inoue S, Ogawa S, Horie K , et al. An estrogen receptor beta isoform that lacks exon 5 has dominant negative activity on both ERalpha and ERbeta. Biochem Biophys Res Commun 2000; 279 (3) 814-819
• 47 Zhao C, Matthews J, Tujague M , et al. Estrogen receptor beta2 negatively regulates the transactivation of estrogen receptor alpha in human breast cancer cells. Cancer Res 2007; 67 (8) 3955-3962
• 48 Tateishi Y, Sonoo R, Sekiya Y , et al. Turning off estrogen receptor beta-mediated transcription requires estrogen-dependent receptor proteolysis. Mol Cell Biol 2006; 26 (21) 7966-7976
• 49 Bhat RA, Harnish DC, Stevis PE, Lyttle CR, Komm BS. A novel human estrogen receptor beta: identification and functional analysis of additional N-terminal amino acids. J Steroid Biochem Mol Biol 1998; 67 (3) 233-240
• 50 Gilmore TD, Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 2006; 25 (51) 6887-6899
• 51 Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol 2008; 180 (1) 630-636
• 52 Harris HA, Albert LM, Leathurby Y , et al. Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology 2003; 144 (10) 4241-4249
• 53 Skliris GP, Munot K, Bell SM , et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol 2003; 201 (2) 213-220
• 54 Esslimani-Sahla M, Kramar A, Simony-Lafontaine J, Warner M, Gustafsson JA, Rochefort H. Increased estrogen receptor betacx expression during mammary carcinogenesis. Clin Cancer Res 2005; 11 (9) 3170-3174
• 55 Omoto Y, Kobayashi S, Inoue S , et al. Evaluation of oestrogen receptor beta wild-type and variant protein expression, and relationship with clinicopathological factors in breast cancers. Eur J Cancer 2002; 38 (3) 380-386
• 56 Leygue E, Dotzlaw H, Watson PH, Murphy LC. Expression of estrogen receptor beta1, beta2, and beta5 messenger RNAs in human breast tissue. Cancer Res 1999; 59 (6) 1175-1179
• 57 Leygue E, Dotzlaw H, Watson PH, Murphy LC. Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis. Cancer Res 1998; 58 (15) 3197-3201
• 58 Brett D, Pospisil H, Valcárcel J, Reich J, Bork P. Alternative splicing and genome complexity. Nat Genet 2002; 30 (1) 29-30
• 59 Lemischka IR, Pritsker M. Alternative splicing increases complexity of stem cell transcriptome. Cell Cycle 2006; 5 (4) 347-351
• 60 Modrek B, Lee C. A genomic view of alternative splicing. Nat Genet 2002; 30 (1) 13-19
• 61 Roberts GC, Smith CW. Alternative splicing: combinatorial output from the genome. Curr Opin Chem Biol 2002; 6 (3) 375-383
• 62 Wessagowit V, Nalla VK, Rogan PK, McGrath JA. Normal and abnormal mechanisms of gene splicing and relevance to inherited skin diseases. J Dermatol Sci 2005; 40 (2) 73-84
• 63 Gallo JM, Jin P, Thornton CA , et al. The role of RNA and RNA processing in neurodegeneration. J Neurosci 2005; 25 (45) 10372-10375
• 64 Lee CJ, Irizarry K. Alternative splicing in the nervous system: an emerging source of diversity and regulation. Biol Psychiatry 2003; 54 (8) 771-776
• 65 Hall PA, Russell SH. New perspectives on neoplasia and the RNA world. Hematol Oncol 2005; 23 (2) 49-53
• 66 Kalnina Z, Zayakin P, Silina K, Linē A. Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 2005; 42 (4) 342-357
• 67 Cummings M, Iremonger J, Green CA, Shaaban AM, Speirs V. Gene expression of ERbeta isoforms in laser microdissected human breast cancers: implications for gene expression analyses. Cell Oncol 2009; 31 (6) 467-473
• 68 Honma N, Horii R, Iwase T , et al. Clinical importance of estrogen receptor-beta evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol 2008; 26 (22) 3727-3734
• 69 Gruvberger-Saal SK, Bendahl PO, Saal LH , et al. Estrogen receptor beta expression is associated with tamoxifen response in ERalpha-negative breast carcinoma. Clin Cancer Res 2007; 13 (7) 1987-1994
• 70 Palmieri C, Lam EW, Mansi J , et al. The expression of ER beta cx in human breast cancer and the relationship to endocrine therapy and survival. Clin Cancer Res 2004; 10 (7) 2421-2428
• 71 Miller WR, Anderson TJ, Dixon JM, Saunders PT. Oestrogen receptor beta and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment. Br J Cancer 2006; 94 (9) 1333-1338
• 72 Sugiura H, Toyama T, Hara Y , et al. Expression of estrogen receptor beta wild-type and its variant ERbetacx/beta2 is correlated with better prognosis in breast cancer. Jpn J Clin Oncol 2007; 37 (11) 820-828
• 73 Esslimani-Sahla M, Simony-Lafontaine J, Kramar A , et al. Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clin Cancer Res 2004; 10 (17) 5769-5776
• 74 Yamashita H, Takahashi S, Ito Y , et al. Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer. Cancer Sci 2009; 100 (11) 2028-2033
• 75 Motomura K, Ishitobi M, Komoike Y , et al. Expression of estrogen receptor beta and phosphorylation of estrogen receptor alpha serine 167 correlate with progression-free survival in patients with metastatic breast cancer treated with aromatase inhibitors. Oncology 2010; 79 (1-2) 55-61
• 76 Novelli F, Milella M, Melucci E , et al. A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study. Breast Cancer Res 2008; 10 (5) R74
• 77 Perou CM, Sørlie T, Eisen MB , et al. Molecular portraits of human breast tumours. Nature 2000; 406 (6797) 747-752
• 78 Wu X, Subramaniam M, Grygo SB , et al. Estrogen receptor-beta sensitizes breast cancer cells to the anti-estrogenic actions of endoxifen. Breast Cancer Res 2011; 13 (2) R27
• 79 Jensen EV, Cheng G, Palmieri C , et al. Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci U S A 2001; 98 (26) 15197-15202
• 80 Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003; 21 (10) 1973-1979
• 81 Foekens JA, van Putten WL, Portengen H , et al. Prognostic value of PS2 and cathepsin D in 710 human primary breast tumors: multivariate analysis. J Clin Oncol 1993; 11 (5) 899-908
• 82 Zhao C, Gao H, Liu Y , et al. Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1. Cancer Res 2010; 70 (12) 5174-5183
• 83 Grober OM, Mutarelli M, Giurato G , et al. Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation. BMC Genomics 2011; 12: 36
• 84 Secreto FJ, Monroe DG, Dutta S, Ingle JN, Spelsberg TC. Estrogen receptor alpha/beta isoforms, but not betacx, modulate unique patterns of gene expression and cell proliferation in Hs578T cells. J Cell Biochem 2007; 101 (5) 1125-1147
• 85 Bierie B, Moses HL. Gain or loss of TGFbeta signaling in mammary carcinoma cells can promote metastasis. Cell Cycle 2009; 8 (20) 3319-3327
• 86 Horvath LG, Henshall SM, Lee C-S , et al. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res 2001; 61 (14) 5331-5335
• 87 Williams C, Edvardsson K, Lewandowski SA, Ström A, Gustafsson JA. A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells. Oncogene 2008; 27 (7) 1019-1032
• 88 Charn TH, Liu ET, Chang EC, Lee YK, Katzenellenbogen JA, Katzenellenbogen BS. Genome-wide dynamics of chromatin binding of estrogen receptors alpha and beta: mutual restriction and competitive site selection. Mol Endocrinol 2010; 24 (1) 47-59
• 89 Carder PJ, Murphy CE, Dervan P , et al. A multi-centre investigation towards reaching a consensus on the immunohistochemical detection of ERbeta in archival formalin-fixed paraffin embedded human breast tissue. Breast Cancer Res Treat 2005; 92 (3) 287-293
• 90 Mann S, Laucirica R, Carlson N , et al. Estrogen receptor beta expression in invasive breast cancer. Hum Pathol 2001; 32 (1) 113-118
• 91 Murphy LC, Leygue E, Niu Y, Snell L, Ho S-M, Watson PH. Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer. Br J Cancer 2002; 87 (12) 1411-1416
• 92 Omoto Y, Inoue S, Ogawa S , et al. Clinical value of the wild-type estrogen receptor beta expression in breast cancer. Cancer Lett 2001; 163 (2) 207-212
• 93 Iwase H, Zhang Z, Omoto Y , et al. Clinical significance of the expression of estrogen receptors alpha and beta for endocrine therapy of breast cancer. Cancer Chemother Pharmacol 2003; 52 (Suppl 1) S34-S38
• 94 Hopp TA, Weiss HL, Parra IS, Cui Y, Osborne CK, Fuqua SA. Low levels of estrogen receptor beta protein predict resistance to tamoxifen therapy in breast cancer. Clin Cancer Res 2004; 10 (22) 7490-7499
• 95 Fleming FJ, Hill AD, McDermott EW, O’Higgins NJ, Young LS. Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. J Clin Endocrinol Metab 2004; 89 (1) 375-383
• 96 Myers E, Fleming FJ, Crotty TB , et al. Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer. Br J Cancer 2004; 91 (9) 1687-1693
• 97 Nakopoulou L, Lazaris AC, Panayotopoulou EG , et al. The favourable prognostic value of oestrogen receptor beta immunohistochemical expression in breast cancer. J Clin Pathol 2004; 57 (5) 523-528
• 98 Saji S, Omoto Y, Shimizu C , et al. Clinical impact of assay of estrogen receptor beta cx in breast cancer. Breast Cancer 2002; 9 (4) 303-307
• 99 Vinayagam R, Sibson DR, Holcombe C, Aachi V, Davies MP. Association of oestrogen receptor beta 2 (ER beta 2/ER beta cx) with outcome of adjuvant endocrine treatment for primary breast cancer—a retrospective study. BMC Cancer 2007; 7: 131
• 100 Maehle BO, Collett K, Tretli S, Akslen LA, Grotmol T. Estrogen receptor beta—an independent prognostic marker in estrogen receptor alpha and progesterone receptor-positive breast cancer?. APMIS 2009; 117 (9) 644-650