Estrogen receptor beta

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Estrogen receptor beta (ER-β), also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2), is one of two main types of estrogen receptor, a nuclear receptor which is activated by the sex hormone estrogen.[1] In humans, ER-β is encoded by the ESR2 gene.[2]


ER-β is a member of the family of estrogen receptors and the superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor α that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.[3]

ER-β may have anti-proliferative effects and therefore oppose the actions of ERα in reproductive tissue.[4] ER-β may also have an important role in adaptive function of the lung during pregnancy.[5]

ER-β is a potent tumor suppressor and plays a crucial role in many cancer types such as prostate cancer.[6][7]

Tissue distribution

ER-β is expressed by many tissues including the uterus,[8] blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER-β is found throughout the brain at different concentrations in different neuron clusters.[9][10]

ER-β abnormalities

ER-β function is related to various cardiovascular targets including ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1). Polymorphism may affect ER-β function and lead to altered responses in postmenopausal women receiving hormone replacement therapy.[11] Abnormalities in gene expression associated with ER-β have also been linked to autism spectrum disorder.[12]


Cardiovascular Disease

Mutations in ERβ have been shown to influence cardiomyocytes, the cells that comprise the largest part of the heart, and can lead to an increased risk of cardiovascular disease (CVD). There is a disparity in prevalence of CVD between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Many types of ERβ receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17βE2 (a naturally occurring estrogen) specifically improves cardiac metabolism. The heart utilizes a lot of energy in the form of ATP to properly pump blood and maintain physiological requirements in order to live, and 17βE2 helps by increasing these myocardial ATP levels and respiratory function.[13]

In addition, 17βE2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ERβ signaling pathway plays a role in both vasodilation and arterial dilation, which contributes to an individual having a healthy heart rate and a decrease in blood pressure. This regulation can increase endothelial function and arterial perfusion, both of which are important to myocyte health. Thus, alterations in this signaling pathways due to ERβ mutation could lead to myocyte cell death from physiological stress. While ERα has a more profound role in regeneration after myocyte cell death, ERβ can still help by increasing endothelial progenitor cell activation and subsequent cardiac function.[14]

Alzheimer's Disease

Genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing Alzheimer’s disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. ERβ mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of amyloid beta peptide (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating insulin-degrading enzyme (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up.[15]

ERβ also plays a role in regulating APOE, a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain.[16]

Neuroprotective Benefits

Synaptic Strength and Plasticity

ERβ levels can dictate both synaptic strength and neuroplasticity through neural structure modifications. Variations in endogenous estrogen levels cause changes in dendritic architecture in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and long-term potentiation (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength. Furthermore, 17βE2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment.[17][18]





Agonists of ER-β selective over ERα include:




Antagonists of ER-β selective over ERα include:


Estrogen receptor beta has been shown to interact with:


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  11. Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (January–February 2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.
  12. Crider A, Thakkar R, Ahmed AO, Pillai A (9 September 2014). "Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects". Molecular Autism. 5 (1): 46. doi:10.1186/2040-2392-5-46. PMID 25221668.
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  14. Muka T, Vargas KG, Jaspers L, Wen KX, Dhana K, Vitezova A, Nano J, Brahimaj A, Colpani V, Bano A, Kraja B, Zaciragic A, Bramer WM, van Dijk GM, Kavousi M, Franco OH (April 2016). "Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies". Maturitas. 86: 28–43. doi:10.1016/j.maturitas.2016.01.009. PMID 26921926.
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  22. Nakamura Y, Felizola SJ, Kurotaki Y, Fujishima F, McNamara KM, Suzuki T, Arai Y, Sasano H (May 2013). "Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer". The Prostate. 73 (6): 590–5. doi:10.1002/pros.22599. PMID 23060014.
  23. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (February 1998). "The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro". Biochemical and Biophysical Research Communications. 243 (1): 122–6. doi:10.1006/bbrc.1997.7893. PMID 9473491.
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  28. Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW (January 2002). "Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs". Molecular Endocrinology. 16 (1): 128–40. doi:10.1210/mend.16.1.0755. PMID 11773444.
  29. Jung DJ, Na SY, Na DS, Lee JW (January 2002). "Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors". The Journal of Biological Chemistry. 277 (2): 1229–34. doi:10.1074/jbc.M110417200. PMID 11704680.
  30. Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F (October 2000). "Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation". The EMBO Journal. 19 (20): 5406–17. doi:10.1093/emboj/19.20.5406. PMC 314017. PMID 11032808.
  31. Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP (October 2000). "Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta". Genomics. 69 (1): 63–71. doi:10.1006/geno.2000.6299. PMID 11013076.

Further reading

  • Pettersson K, Gustafsson JA (2001). "Role of estrogen receptor beta in estrogen action". Annual Review of Physiology. 63: 165–92. doi:10.1146/annurev.physiol.63.1.165. PMID 11181953.
  • Warner M, Saji S, Gustafsson JA (July 2000). "The normal and malignant mammary gland: a fresh look with ER beta onboard". Journal of Mammary Gland Biology and Neoplasia. 5 (3): 289–94. doi:10.1023/A:1009598828267. PMID 14973391.
  • Saxon LK, Turner CH (February 2005). "Estrogen receptor beta: the antimechanostat?". Bone. 36 (2): 185–92. doi:10.1016/j.bone.2004.08.003. PMID 15780944.
  • Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M (June 1994). "Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription". Science. 264 (5164): 1455–8. doi:10.1126/science.8197458. PMID 8197458.
  • Schwabe JW, Chapman L, Finch JT, Rhodes D (November 1993). "The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements". Cell. 75 (3): 567–78. doi:10.1016/0092-8674(93)90390-C. PMID 8221895.
  • Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (August 1997). "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300". Cell. 90 (3): 569–80. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036.
  • Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S (October 1997). "Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha". The Journal of Biological Chemistry. 272 (41): 25832–8. doi:10.1074/jbc.272.41.25832. PMID 9325313.
  • Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB (October 1997). "Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus". The Journal of Clinical Endocrinology and Metabolism. 82 (10): 3509–12. doi:10.1210/jc.82.10.3509. PMID 9329394.
  • Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA (December 1997). "Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern". The Journal of Clinical Endocrinology and Metabolism. 82 (12): 4258–65. doi:10.1210/jc.82.12.4258. PMID 9398750.
  • Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R (January 1998). "Expression of estrogen receptor beta messenger RNA variant in breast cancer". Cancer Research. 58 (2): 210–4. PMID 9443393.
  • Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (February 1998). "The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro". Biochemical and Biophysical Research Communications. 243 (1): 122–6. doi:10.1006/bbrc.1997.7893. PMID 9473491.
  • Alves SE, Lopez V, McEwen BS, Weiland NG (March 1998). "Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study". Proceedings of the National Academy of Sciences of the United States of America. 95 (6): 3281–6. doi:10.1073/pnas.95.6.3281. PMC 19733. PMID 9501254.
  • Brandenberger AW, Tee MK, Jaffe RB (March 1998). "Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues". The Journal of Clinical Endocrinology and Metabolism. 83 (3): 1025–8. doi:10.1210/jc.83.3.1025. PMID 9506768.
  • Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM (June 1998). "Cloning and characterization of human estrogen receptor beta isoforms". Biochemical and Biophysical Research Communications. 247 (1): 75–8. doi:10.1006/bbrc.1998.8738. PMID 9636657.
  • Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (August 1998). "Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human". Nucleic Acids Research. 26 (15): 3505–12. doi:10.1093/nar/26.15.3505. PMC 147730. PMID 9671811.
  • Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, Watson PH (March 1998). "Estrogen receptor-beta mRNA variants in human and murine tissues". Molecular and Cellular Endocrinology. 138 (1–2): 199–203. doi:10.1016/S0303-7207(98)00050-1. PMID 9685228.
  • Seol W, Hanstein B, Brown M, Moore DD (October 1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Molecular Endocrinology. 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
  • Hanstein B, Liu H, Yancisin MC, Brown M (January 1999). "Functional analysis of a novel estrogen receptor-beta isoform". Molecular Endocrinology. 13 (1): 129–37. doi:10.1210/me.13.1.129. PMID 9892018.
  • Vidal O, Kindblom LG, Ohlsson C (June 1999). "Expression and localization of estrogen receptor-beta in murine and human bone". Journal of Bone and Mineral Research. 14 (6): 923–9. doi:10.1359/jbmr.1999.14.6.923. PMID 10352100.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.