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Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy

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Abstract

Introduction

Ovarian cancer remains the leading cause of mortality due to gynecological tumors. Estrogen receptors (ERs) seem to participate in tumor progression even in the absence of estrogens. Twenty years after the cloning of the second estrogen receptor, a wide spectrum of studies have shown its implication in both physiologic and pathologic pathways. ERβ, being the predominant type of ER in normal ovary tissue, has not only been linked with pathogenesis of ovarian cancer, but also with response to treatment. Unlike ERα, which is primarily linked with cell growth, ERβ presence is prominent in signaling pathways, cell cycle regulation and apoptosis.

Methods

Literature review of relevant published material (from PubMed, Scopus, and Cochrane databases) was conducted.

Results

Polymorphisms in the respective ESR2 gene, epigenetic modifications and isoforms of the receptor have been extensively studied to assess potential correlations with responsiveness to treatment and tumor behavior. Studies on the exact roles of ERβ and its genetic variations in altering effectiveness and toxicity of ovarian cancer treatment regimens are lacking.

Conclusion

Clinical utilization of ERβ actions in the management of ovarian cancer is discussed in an up-to-date review.

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References

  1. Jia M, Dahlman-Wright K, Gustafsson JÅ (2015) Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab 29(4):557–568. doi:10.1016/j.beem.2015.04.008

    Article  CAS  PubMed  Google Scholar 

  2. Imamov O, Shim GJ, Warner M, Gustafsson JA (2005) Estrogen receptor beta in health and disease. Biol Reprod 73(5):866–871

    Article  CAS  PubMed  Google Scholar 

  3. Heldring N, Pike A, Andersson S et al (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87(3):905–931

    Article  CAS  PubMed  Google Scholar 

  4. Deroo BJ, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116(3):561–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhao C, Dahlman-Wright K, Gustafsson JA (2008) Estrogen receptor beta: an overview and update. Nucl Recept Signal 6:e003. doi:10.1621/nrs.06003

    PubMed  PubMed Central  Google Scholar 

  6. Ciucci A, Zannoni GF, Travaglia D, Scambia G, Gallo D (2015) Mitochondrial estrogen receptor β2 drives antiapoptotic pathways in advanced serous ovarian cancer. Hum Pathol 46(8):1138–1146. doi:10.1016/j.humpath.2015.03.016

    Article  CAS  PubMed  Google Scholar 

  7. Drummond AE, Fuller PJ (2010) The importance of ERbeta signalling in the ovary. J Endocrinol 205(1):15–23. doi:10.1677/JOE-09-0379

    Article  CAS  PubMed  Google Scholar 

  8. Nott SL, Huang Y, Fluharty BR et al (2008) Do estrogen receptor beta polymorphisms play a role in the pharmacogenetics of estrogen signaling? Curr Pharmacogenom Person Med 6(4):239–259

    Article  CAS  Google Scholar 

  9. Lee HR, Kim TH, Choi KC (2012) Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res 28(2):71–76. doi:10.5625/lar.2012.28.2.71

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bossard C, Busson M, Vindrieux D et al (2012) Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer. PLoS One 7(9):e44787. doi:10.1371/journal.pone.0044787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lazennec G (2006) Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis. Cancer Lett 231(2):151–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Docquier A, Garcia A, Savatier J et al (2013) Negative regulation of estrogen signaling by ERβ and RIP140 in ovarian cancer cells. Mol Endocrinol 27(9):1429–1441. doi:10.1210/me.2012-1351

    Article  CAS  PubMed  Google Scholar 

  13. Treeck O, Pfeiler G, Mitter D, Lattrich C, Piendl G, Ortmann O (2007) Estrogen receptor {beta}1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells. J Endocrinol 193(3):421–433

    Article  CAS  PubMed  Google Scholar 

  14. Fekete T, Rásó E, Pete I et al (2012) Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples. Int J Cancer 131(1):95–105. doi:10.1002/ijc.26364

    Article  CAS  PubMed  Google Scholar 

  15. Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P (2004) Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11(3):537–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rutherford T, Brown WD, Sapi E, Aschkenazi S, Muñoz A, Mor G (2000) Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 96(3):417–421

    CAS  PubMed  Google Scholar 

  17. Mendoza N, Morón FJ, Quereda F et al (2008) A digenic combination of polymorphisms within ESR1 and ESR2 genes are associated with age at menarche in the Spanish population. Reprod Sci 15(3):305–311. doi:10.1177/1933719107314064

    Article  PubMed  Google Scholar 

  18. Mendoza N, Sánchez-Borrego R, Galiano D et al (2009) Multigenic combination of estrogen-related genes is associated with age at natural menopause in a Spanish population. Menopause Int 15(4):150–156. doi:10.1258/mi.2009.009043

    PubMed  Google Scholar 

  19. Lau KM, Mok SC, Ho SM (1999) Expression of human estrogen receptor-alpha and -beta, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc Natl Acad Sci USA 96(10):5722–5727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li AJ, Baldwin RL, Karlan BY (2003) Estrogen and progesterone receptor subtype expression in normal and malignant ovarian epithelial cell cultures. Am J Obstet Gynecol 189(1):22–27

    Article  CAS  PubMed  Google Scholar 

  21. Aust S, Horak P, Pils D et al (2013) The prognostic value of estrogen receptor beta and proline-, glutamic acid- and leucine-rich protein 1 (PELP1) expression in ovarian cancer. BMC Cancer 13:115. doi:10.1186/1471-2407-13-115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ciucci A, Zannoni GF, Travaglia D, Petrillo M, Scambia G, Gallo D (2014) Prognostic significance of the estrogen receptor beta (ERβ) isoforms ERβ1, ERβ2, and ERβ5 in advanced serous ovarian cancer. Gynecol Oncol 132(2):351–359. doi:10.1016/j.ygyno.2013.12.027

    Article  CAS  PubMed  Google Scholar 

  23. De Stefano I, Zannoni GF, Prisco MG et al (2011) Cytoplasmic expression of estrogen receptor beta (ERβ) predicts poor clinical outcome in advanced serous ovarian cancer. Gynecol Oncol 122(3):573–579. doi:10.1016/j.ygyno.2011.05.025

    Article  PubMed  Google Scholar 

  24. Hu Z, Zhu L, Tan M et al (2015) The expression and correlation between the transcription factor FOXP1 and estrogen receptors in epithelial ovarian cancer. Biochimie 109:42–48. doi:10.1016/j.biochi.2014.12.001

    Article  CAS  PubMed  Google Scholar 

  25. Burges A, Brüning A, Dannenmann C et al (2010) Prognostic significance of estrogen receptor alpha and beta expression in human serous carcinomas of the ovary. Arch Gynecol Obstet 281(3):511–517. doi:10.1007/s00404-009-1185-y

    Article  CAS  PubMed  Google Scholar 

  26. Lenhard M, Tereza L, Heublein S et al (2012) Steroid hormone receptor expression in ovarian cancer: progesterone receptor B as prognostic marker for patient survival. BMC Cancer 12:553. doi:10.1186/1471-2407-12-553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fujimoto J, Hirose R, Sakaguchi H, Tamaya T (2000) Clinical significance of expression of estrogen receptor alpha and beta mRNAs in ovarian cancers. Oncology 58(4):334–341. doi:10.1159/000012121

    Article  CAS  PubMed  Google Scholar 

  28. van Kruchten M, van der Marel P, de Munck L et al (2015) Hormone receptors as a marker of poor survival in epithelial ovarian cancer. Gynecol Oncol 138(3):634–639. doi:10.1016/j.ygyno.2015.06.032

    Article  PubMed  Google Scholar 

  29. Chan KK, Wei N, Liu SS, Xiao-Yun L, Cheung AN, Ngan HY (2008) Estrogen receptor subtypes in ovarian cancer: a clinical correlation. Obstet Gynecol 111(1):144–151. doi:10.1097/01.AOG.0000296715.07705.e9

    Article  CAS  PubMed  Google Scholar 

  30. Jönsson JM, Skovbjerg Arildsen N, Malander S et al (2015) Sex steroid hormone receptor expression affects ovarian cancer survival. Transl Oncol 8(5):424–433. doi:10.1016/j.tranon.2015.09.002

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhao D, Zhang F, Zhang W, He J, Zhao Y, Sun J (2013) Prognostic role of hormone receptors in ovarian cancer: a systematic review and meta-analysis. Int J Gynecol Cancer 23(1):25–33. doi:10.1097/IGC.0b013e3182788466

    Article  PubMed  Google Scholar 

  32. de Toledo MC, Sarian LO, Sallum LF et al (2014) Analysis of the contribution of immunologically-detectable HER2, steroid receptors and of the “triple-negative” tumor status to disease-free and overall survival of women with epithelial ovarian cancer. Acta Histochem 116(3):440–447. doi:10.1016/j.acthis.2013.09.010

    Article  PubMed  Google Scholar 

  33. Fuller PJ, Chu S (2004) Signalling pathways in the molecular pathogenesis of ovarian granulosa cell tumours. Trends Endocrinol Metab 15(3):122–128

    Article  CAS  PubMed  Google Scholar 

  34. Alexiadis M, Eriksson N, Jamieson S et al (2011) Nuclear receptor profiling of ovarian granulosa cell tumors. Horm Cancer 2(3):157–169. doi:10.1007/s12672-011-0069-3

  35. Hutton SM, Webster LR, Nielsen S, Leung Y, Stewart CJ (2012) Immunohistochemical expression and prognostic significance of oestrogen receptor-alpha, oestrogen receptor-beta, and progesterone receptor in stage 1 adult-type granulosa cell tumour of the ovary. Pathology 44(7):611–616. doi:10.1097/PAT.0b013e328359d636

    Article  CAS  PubMed  Google Scholar 

  36. Figtree GA, Noonan JE, Bhindi R, Collins P (2009) Estrogen receptor polymorphisms: significance to human physiology, disease and therapy. Recent Pat DNA Gene Seq 3(3):164–171

    Article  CAS  PubMed  Google Scholar 

  37. Lurie G, Wilkens LR, Thompson PJ et al (2009) Genetic polymorphisms in the estrogen receptor beta (ESR2) gene and the risk of epithelial ovarian carcinoma. Cancer Causes Control 20(1):47–55. doi:10.1007/s10552-008-9216-8

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ryan J, Canonico M, Carcaillon L et al (2012) Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study. PLoS One 7(3):e34112. doi:10.1371/journal.pone.0034112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dai ZJ, Wang BF, Ma YF et al (2014) Current evidence on the relationship between rs1256049 polymorphism in estrogen receptor-β gene and cancer risk. Int J Clin Exp Med 7(12):5031–5040

    PubMed  PubMed Central  Google Scholar 

  40. Leigh Pearce C, Near AM, Butler JL et al (2008) Comprehensive evaluation of ESR2 variation and ovarian cancer risk. Cancer Epidemiol Biomark Prev 17(2):393–396. doi:10.1158/1055-9965.EPI-07-2512

    Article  CAS  Google Scholar 

  41. Pearce CL, Near AM, Van Den Berg DJ, Australian Cancer Study, Australian Ovarian Cancer Study Group et al (2009) Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. Br J Cancer 100(2):412–420. doi:10.1038/sj.bjc.6604820

  42. Delort L, Chalabi N, Satih S et al (2008) Association between genetic polymorphisms and ovarian cancer risk. Anticancer Res 28(5B):3079–3081

    CAS  PubMed  Google Scholar 

  43. Philips S, Richter A, Oesterreich S et al (2012) Functional characterization of a genetic polymorphism in the promoter of the ESR2 gene. Horm Cancer 3(1–2):37–43. doi:10.1007/s12672-011-0086-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Schüler S, Lattrich C, Skrzypczak M, Fehm T, Ortmann O, Treeck O (2014) Polymorphisms in the promoter region of ESR2 gene and susceptibility to ovarian cancer. Gene 546(2):283–287. doi:10.1016/j.gene.2014.05.066

    Article  PubMed  Google Scholar 

  45. Lurie G, Wilkens LR, Thompson PJ, Goodman MT et al (2011) Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium. PLoS One 6(6):20703. doi:10.1371/journal.pone.0020703

    Article  Google Scholar 

  46. Goulart AC, Zee RY, Rexrode KM (2009) Association of estrogen receptor 2 gene polymorphisms with obesity in women (obesity and estrogen receptor 2 gene). Maturitas 62(2):179–183. doi:10.1016/j.maturitas.2008.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nilsson M, Dahlman I, Jiao H et al (2007) Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis—a cohort study. BMC Med Genet 8:73

    Article  PubMed  PubMed Central  Google Scholar 

  48. Suzuki F, Akahira J, Miura I et al (2008) Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci 99(12):2365–2372. doi:10.1111/j.1349-7006.2008.00988.x

    Article  CAS  PubMed  Google Scholar 

  49. Yap OW, Bhat G, Liu L, Tollefsbol TO (2009) Epigenetic modifications of the estrogen receptor beta gene in epithelial ovarian cancer cells. Anticancer Res 29(1):139–144

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Al-Nakhle H, Smith L, Bell SM et al (2013) Regulation of estrogen receptor β1 expression in breast cancer by epigenetic modification of the 5′ regulatory region. Int J Oncol 43(6):2039–2045. doi:10.3892/ijo.2013.2112

    CAS  PubMed  Google Scholar 

  51. Al-Nakhle H, Burns PA, Cummings M et al (2010) Estrogen receptor {beta}1 expression is regulated by miR-92 in breast cancer. Cancer Res 70(11):4778–4784. doi:10.1158/0008-5472.CAN-09-4104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J (2014) The many faces of estrogen signaling. Biochem Med (Zagreb) 24(3):329–342. doi:10.11613/BM.2014.035

    Article  Google Scholar 

  53. Yamaguchi K, Matsumura N, Mandai M, Baba T, Konishi I, Murphy SK (2014) Epigenetic and genetic dispositions of ovarian carcinomas. Oncoscience 1(9):574–579

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yamaguchi K, Huang Z, Matsumura N et al (2014) Epigenetic determinants of ovarian clear cell carcinoma biology. Int J Cancer 135(3):585–597. doi:10.1002/ijc.28701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alves LN, Wolfgramm EV, de Castro Neto AK, Louro ID (2013) Analysis of microsatellite instability and loss of heterozygosity in ovarian cancer: a study in the population of Espírito Santo, Brazil. Genet Mol Res 12(2):1996–2001. doi:10.4238/2013.June.14.2

    Article  CAS  PubMed  Google Scholar 

  56. Pitta CA, Papageorgis P, Charalambous C, Constantinou AI (2013) Reversal of ER-β silencing by chromatin modifying agents overrides acquired tamoxifen resistance. Cancer Lett 337(2):167–176. doi:10.1016/j.canlet.2013.05.031

    Article  CAS  PubMed  Google Scholar 

  57. Koukoura O, Spandidos DA, Daponte A, Sifakis S (2014) DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (review). Mol Med Rep 10(1):3–9. doi:10.3892/mmr.2014.2221

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Meng F, Sun G, Zhong M, Yu Y, Brewer MA (2013) Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2′-deoxycytidine on ovarian cancer. Br J Cancer 108(3):579–586. doi:10.1038/bjc.2013.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kovats S (2015) Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol 294(2):63–69. doi:10.1016/j.cellimm.2015.01.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Stellato C, Porreca I, Cuomo D, Tarallo R, Nassa G, Ambrosino C (2015) The “busy life” of unliganded estrogen receptors. Proteomics. doi:10.1002/pmic.201500261

    Google Scholar 

  61. Martinez-Arguelles DB, Papadopoulos V (2010) Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action. Steroids 75(7):467–476. doi:10.1016/j.steroids.2010.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zama AM, Uzumcu M (2009) Fetal and neonatal exposure to the endocrine disruptor methoxychlor causes epigenetic alterations in adult ovarian genes. Endocrinology 150(10):4681–4691. doi:10.1210/en.2009-0499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Karmaus W, Osuch JR, Landgraf J, Taffe B, Mikucki D, Haan P (2011) Prenatal and concurrent exposure to halogenated organic compounds and gene expression of CYP17A1, CYP19A1, and oestrogen receptor alpha and beta genes. Occup Environ Med 68(6):430–437. doi:10.1136/oem.2009.053249

    Article  CAS  PubMed  Google Scholar 

  64. Mahmoud AM, Al-Alem U, Ali MM, Bosland MC (2015) Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation. J Steroid Biochem Mol Biol 152:62–75. doi:10.1016/j.jsbmb.2015.04.018

    Article  CAS  PubMed  Google Scholar 

  65. Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011) Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy. Genet Test Mol Biomark 15(1–2):11–15. doi:10.1089/gtmb.2010.0106

    Article  CAS  Google Scholar 

  66. Halon A, Nowak-Markwitz E, Maciejczyk A et al (2011) Loss of estrogen receptor beta expression correlates with shorter overall survival and lack of clinical response to chemotherapy in ovarian cancer patients. Anticancer Res 31(2):711–718

    CAS  PubMed  Google Scholar 

  67. Pons DG, Sastre-Serra J, Nadal-Serrano M et al (2012) Initial activation status of the antioxidant response determines sensitivity to carboplatin/paclitaxel treatment of ovarian cancer. Anticancer Res 32(11):4723–4728

    CAS  PubMed  Google Scholar 

  68. Marsh S (2009) Pharmacogenomics of taxane/platinum therapy in ovarian cancer. Int J Gynecol Cancer 19(Suppl 2):S30–S34. doi:10.1111/IGC.0b013e3181c10513

    Article  PubMed  Google Scholar 

  69. Pawlik A, Dziedziejko V, Kurzawski M, Safranow K, Kotrych D, Bohatyrewicz A (2012) Effect of ESR1 and ESR2 gene polymorphisms on rheumatoid arthritis treatment with methotrexate. Pharmacol Rep 64(1):185–190

    Article  CAS  PubMed  Google Scholar 

  70. Dziedziejko V, Kurzawski M, Safranow K, Chlubek D, Pawlik A (2011) The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 12(1):41–47. doi:10.2217/pgs.10.164

    Article  CAS  PubMed  Google Scholar 

  71. Henry NL, Nguyen A, Azzouz F et al (2010) Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy. Br J Cancer 102(2):294–300. doi:10.1038/sj.bjc.6605460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jin Y, Hayes DF, Li L et al (2008) Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol 26(36):5849–5854. doi:10.1200/JCO.2008.16.8377

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ribeiro JR, Freiman RN (2014) Estrogen signaling crosstalk: implications for endocrine resistance in ovarian cancer. J Steroid Biochem Mol Biol 143:160–173. doi:10.1016/j.jsbmb.2014.02.010

    Article  CAS  PubMed  Google Scholar 

  74. National Center for Biotechnology Information, US National Library of Medicine (2015). http://www.ncbi.nlm.nih.gov/projects/SNP/. Accessed 7 Nov 2015

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  1. Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Stilpon Kyriakidis Street 1, 546 36, Thessaloniki, Greece

    Ioannis Kyriakidis & Paraskevi Papaioannidou

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  1. Ioannis Kyriakidis
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Correspondence to Ioannis Kyriakidis.

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Kyriakidis, I., Papaioannidou, P. Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy. Arch Gynecol Obstet 293, 1161–1168 (2016). https://doi.org/10.1007/s00404-016-4027-8

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