Biology:Estrogen receptor beta

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Estrogen receptor beta (ERβ) 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 ERβ is encoded by the ESR2 gene.[2]

Function

ERβ 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]

ERβ may inhibit cell proliferation and opposes the actions of ERα in reproductive tissue.[4] ERβ may also have an important role in adaptive function of the lung during pregnancy.[5]

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

Mammary gland

ERβ knockout mice show normal mammary gland development at puberty and are able to lactate normally.[8][9][10] The mammary glands of adult virgin female mice are indistinguishable from those of age-matched wild-type virgin female mice.[8] This is in contrast to ERα knockout mice, in which a complete absence of mammary gland development at puberty and thereafter is observed.[8][10] Administration of the selective ERβ agonist ERB-041 to immature ovariectomized female rats produced no observable effects in the mammary glands, further indicating that the ERβ is non-mammotrophic.[11][10][12]

Although ERβ is not required for pubertal development of the mammary glands, it may be involved in terminal differentiation in pregnancy, and may also be necessary to maintain the organization and differentiation of mammary epithelium in adulthood.[13][14] In old female ERβ knockout mice, severe cystic mammary disease that is similar in appearance to postmenopausal mastopathy develops, whereas this does not occur in aged wild-type female mice.[9] However, ERβ knockout mice are not only deficient in ERβ signaling in the mammary glands, but also have deficient progesterone exposure due to impairment of corpora lutea formation.[9][13] This complicates attribution of the preceding findings to mammary ERβ signaling.[9][13]

Selective ERβ agonism with diarylpropionitrile (DPN) has been found to counteract the proliferative effects in the mammary glands of selective ERα agonism with propylpyrazoletriol (PPT) in ovariectomized postmenopausal female rats.[15][16] Similarly, overexpression of ERβ via lentiviral infection in mature virgin female rats decreases mammary proliferation.[16] ERα signaling has proliferative effects in both normal breast and breast cancer cell lines, whereas ERβ has generally antiproliferative effects in such cell lines.[13] However, ERβ has been found to have proliferative effects in some breast cell lines.[13]

Expression of ERα and ERβ in the mammary gland have been found to vary throughout the menstrual cycle and in an ovariectomized state in female rats.[16] Whereas mammary ERα in rhesus macaques is downregulated in response to increased estradiol levels, expression of ERβ in the mammary glands is not.[17] Expression of ERα and ERβ in the mammary glands also differs throughout life in female mice.[18] Mammary ERα expression is higher and mammary ERβ expression lower in younger female mice, while mammary ERα expression is lower and mammary ERβ expression higher in older female mice as well as in parous female mice.[18] Mammary proliferation and estrogen sensitivity is higher in young female mice than in old or parous female mice, particularly during pubertal mammary gland development.[18]

Tissue distribution

ERβ is expressed by many tissues including the uterus,[19] blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ERβ is found throughout the brain at different concentrations in different neuron clusters.[20][21] ERβ is also highly expressed in normal breast epithelium, although its expression declines with cancer progression.[22] ERβ is expressed in all subtypes of breast cancer.[23] Controversy regarding ERβ protein expression has hindered study of ERβ, but highly sensitive monoclonal antibodies have been produced and well-validated to address these issues.[24]

ERβ abnormalities

ERβ function is related to various cardiovascular targets including ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1). Polymorphism may affect ERβ function and lead to altered responses in postmenopausal women receiving hormone replacement therapy.[25] Abnormalities in gene expression associated with ERβ have also been linked to autism spectrum disorder.[26]

Disease

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.[27]

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.[28]

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.[29]

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.[30]

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.[31][32]

Ligands

Agonists

Non-selective

Selective

Agonists of ERβ selective over ERα include:



Antagonists

Non-selective

Selective

Antagonists of ERβ selective over ERα include:

Affinities

Interactions

Estrogen receptor beta has been shown to interact with:


References

  1. ↑ "Cloning of a novel receptor expressed in rat prostate and ovary". Proceedings of the National Academy of Sciences of the United States of America 93 (12): 5925–5930. June 1996. doi:10.1073/pnas.93.12.5925. PMID 8650195. 
  2. ↑ "ER beta: identification and characterization of a novel human estrogen receptor". FEBS Letters 392 (1): 49–53. August 1996. doi:10.1016/0014-5793(96)00782-X. PMID 8769313. 
  3. ↑ "Entrez Gene: ESR2 estrogen receptor 2 (ER beta)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2100. 
  4. ↑ "Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus". Proceedings of the National Academy of Sciences of the United States of America 97 (11): 5936–5941. May 2000. doi:10.1073/pnas.97.11.5936. PMID 10823946. Bibcode: 2000PNAS...97.5936W. 
  5. ↑ "The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies". American Journal of Physiology. Lung Cellular and Molecular Physiology 293 (2): L272–L278. August 2007. doi:10.1152/ajplung.00174.2007. PMID 17575008. 
  6. ↑ "The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment". Molecular Cancer Therapeutics 6 (10): 2626–2633. October 2007. doi:10.1158/1535-7163.MCT-07-0197. PMID 17913855. 
  7. ↑ "Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy". Archives of Gynecology and Obstetrics 293 (6): 1161–1168. June 2016. doi:10.1007/s00404-016-4027-8. PMID 26861465. 
  8. ↑ 8.0 8.1 8.2 "Estrogen receptor null mice: what have we learned and where will they lead us?". Endocrine Reviews 20 (3): 358–417. June 1999. doi:10.1210/edrv.20.3.0370. PMID 10368776. 
  9. ↑ 9.0 9.1 9.2 9.3 "Estrogen receptor beta in the breast: role in estrogen responsiveness and development of breast cancer". The Journal of Steroid Biochemistry and Molecular Biology 74 (5): 245–248. November 2000. doi:10.1016/S0960-0760(00)00130-8. PMID 11162931. 
  10. ↑ 10.0 10.1 10.2 "Estrogen Receptors: Their Actions and Functional Roles in Health and Disease". Nuclear Receptors. 2010. pp. 91–141. doi:10.1007/978-90-481-3303-1_5. ISBN 978-90-481-3302-4. 
  11. ↑ "Estrogen receptors: therapies targeted to receptor subtypes". Clinical Pharmacology and Therapeutics 89 (1): 44–55. January 2011. doi:10.1038/clpt.2010.226. PMID 21124311. 
  12. ↑ "Evaluation of an estrogen receptor-beta agonist in animal models of human disease". Endocrinology 144 (10): 4241–4249. October 2003. doi:10.1210/en.2003-0550. PMID 14500559. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "Estrogen Receptor β and Breast Cancer". Cancer Drug Discovery and Development: pp. 309–342. 2019. doi:10.1007/978-3-319-99350-8_12. ISBN 978-3-319-99349-2. ISSN 2196-9906. 
  14. ↑ "Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS". Journal of Molecular Endocrinology 51 (3): T61–T74. December 2013. doi:10.1530/JME-13-0150. PMID 24031087. 
  15. ↑ "Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats". The Journal of Steroid Biochemistry and Molecular Biology 130 (1–2): 26–35. May 2012. doi:10.1016/j.jsbmb.2011.12.018. PMID 22266284. 
  16. ↑ 16.0 16.1 16.2 Song, X. (2014). Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation. Graduate College Dissertations and Theses. 259. https://scholarworks.uvm.edu/graddis/259
  17. ↑ "Differential regulation of estrogen receptor (ER)alpha and ERbeta in primate mammary gland". The Journal of Clinical Endocrinology and Metabolism 90 (1): 435–444. January 2005. doi:10.1210/jc.2004-0861. PMID 15507513. 
  18. ↑ 18.0 18.1 18.2 "Estrogen receptor subtypes dictate the proliferative nature of the mammary gland". The Journal of Endocrinology 237 (3): 323–336. June 2018. doi:10.1530/JOE-17-0582. PMID 29636363. 
  19. ↑ "Estrogen receptor β: the guardian of the endometrium". Human Reproduction Update 21 (2): 174–193. Mar 2015. doi:10.1093/humupd/dmu053. PMID 25305176. 
  20. ↑ "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology 138 (11): 4613–4621. November 1997. doi:10.1210/endo.138.11.5496. PMID 9348186. 
  21. ↑ "Reflections on the discovery and significance of estrogen receptor beta". Endocrine Reviews 26 (3): 465–478. May 2005. doi:10.1210/er.2004-0027. PMID 15857973. 
  22. ↑ "Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis". Cancer Research 58 (15): 3197–3201. August 1998. PMID 9699641. 
  23. ↑ "ERβ1: characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer". BMC Cancer 14 (749): 749. October 2014. doi:10.1186/1471-2407-14-749. PMID 25288324. 
  24. ↑ "Optimized immunohistochemical detection of estrogen receptor beta using two validated monoclonal antibodies confirms its expression in normal and malignant breast tissues". Breast Cancer Research and Treatment 179 (1): 241–249. January 2020. doi:10.1007/s10549-019-05441-3. PMID 31571071. 
  25. ↑ "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): 11–15. January–February 2011. doi:10.1089/gtmb.2010.0106. PMID 21117950. 
  26. ↑ "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. 9 September 2014. doi:10.1186/2040-2392-5-46. PMID 25221668. 
  27. ↑ "The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview". The Canadian Journal of Cardiology 32 (8): 1017–1025. August 2016. doi:10.1016/j.cjca.2015.10.021. PMID 26860777. 
  28. ↑ "Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies". Maturitas 86: 28–43. April 2016. doi:10.1016/j.maturitas.2016.01.009. PMID 26921926. 
  29. ↑ "Brain sex matters: estrogen in cognition and Alzheimer's disease". Molecular and Cellular Endocrinology 389 (1–2): 13–21. May 2014. doi:10.1016/j.mce.2013.12.018. PMID 24418360. 
  30. ↑ "Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics". Ageing Research Reviews 24 (Pt B): 178–190. November 2015. doi:10.1016/j.arr.2015.08.001. PMID 26307455. 
  31. ↑ "Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury". Progress in Neurobiology 157: 188–211. October 2017. doi:10.1016/j.pneurobio.2015.12.008. PMID 26891883. 
  32. ↑ "The functions of estrogen receptor beta in the female brain: A systematic review". Maturitas 93: 41–57. November 2016. doi:10.1016/j.maturitas.2016.05.014. PMID 27338976. 
  33. ↑ Maria Kristina Parr; Piwen Zhao; Oliver Haupt; Sandrine Tchoukouegno Ngueu; Jonas Hengevoss; Karl Heinrich Fritzemeier; Marion Piechotta; Nils Schlörer et al. (2014). "Estrogen receptor beta is involved in skeletal muscle hypertrophy induced by the phytoecdysteroid ecdysterone". Molecular Nutrition & Food Research 58 (9): 1861–1872. doi:10.1002/mnfr.201300806. PMID 24974955. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 "Botanical modulation of menopausal symptoms: mechanisms of action?". Planta Medica 79 (7): 538–553. May 2013. doi:10.1055/s-0032-1328187. PMID 23408273. 
  35. ↑ "Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta". Journal of Medicinal Chemistry 52 (3): 858–867. February 2009. doi:10.1021/jm801458t. PMID 19128016. 
  36. ↑ "Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists". Molecular Pharmacology 54 (1): 105–112. July 1998. doi:10.1124/mol.54.1.105. PMID 9658195. 
  37. ↑ "Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer". The Prostate 73 (6): 590–595. May 2013. doi:10.1002/pros.22599. PMID 23060014. 
  38. ↑ "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): 122–126. February 1998. doi:10.1006/bbrc.1997.7893. PMID 9473491. 
  39. ↑ 39.0 39.1 "Specific association of estrogen receptor beta with the cell cycle spindle assembly checkpoint protein, MAD2". Proceedings of the National Academy of Sciences of the United States of America 97 (6): 2836–2839. March 2000. doi:10.1073/pnas.050580997. PMID 10706629. Bibcode: 2000PNAS...97.2836P. 
  40. ↑ "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry 40 (23): 6756–6765. June 2001. doi:10.1021/bi010379h. PMID 11389589. 
  41. ↑ "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3". The Journal of Biological Chemistry 275 (8): 5976–5982. February 2000. doi:10.1074/jbc.275.8.5976. PMID 10681591. 
  42. ↑ "Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2". Molecular Endocrinology 15 (2): 241–254. February 2001. doi:10.1210/mend.15.2.0595. PMID 11158331. 
  43. ↑ "Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs". Molecular Endocrinology 16 (1): 128–140. January 2002. doi:10.1210/mend.16.1.0755. PMID 11773444. 
  44. ↑ "Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors". The Journal of Biological Chemistry 277 (2): 1229–1234. January 2002. doi:10.1074/jbc.M110417200. PMID 11704680. 
  45. ↑ "Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation". The EMBO Journal 19 (20): 5406–5417. October 2000. doi:10.1093/emboj/19.20.5406. PMID 11032808. 
  46. ↑ "Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta". Genomics 69 (1): 63–71. October 2000. doi:10.1006/geno.2000.6299. PMID 11013076. 

Further reading

External links

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