Biology:GPER

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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


G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene.[1] GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.[2]

Discovery

The classical estrogen receptors first characterized in 1958[3] are water-soluble proteins located in the interior of cells that are activated by estrogenenic hormones such as estradiol and several of its metabolites such as estrone or estriol. These proteins belong to the nuclear hormone receptor class of transcription factors that regulate gene transcription. Since it takes time for genes to be transcribed into RNA and translated into protein, the effects of estrogens binding to these classical estrogen receptors is delayed. However, estrogens are also known to have effects that are too fast to be caused by regulation of gene transcription.[4] In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) family, GPR30 also binds with high affinity to estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor (GPER). GPER is localized in the plasma membrane but is predominantly detected in the endoplasmic reticulum.[5][4]

Ligands

GPER binds estradiol with high affinity though not other endogenous estrogens, such as estrone or estriol, nor other endogenous steroids, including progesterone, testosterone, and cortisol.[2][5][6][7][8] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone.[2][9][10] Niacin and nicotinamide bind to the receptor in vitro with very low affinity.[11][12] CCL18 has been identified as an endogenous antagonist of the GPER.[13] GPER-selective ligands (that do not bind the classical estrogen receptors) include the agonist G-1[14] and the antagonists G15[15] and G36.[16][2]

Agonists

Antagonists

Unknown

Non-ligand

Function

This protein is a member of the rhodopsin-like family of G protein-coupled receptors and is a multi-pass membrane protein that localizes to the plasma membrane. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus.[5] This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol.[17] The distribution of GPER is well established in the rodent, with high expression observed in the hypothalamus, pituitary gland, adrenal medulla, kidney medulla and developing follicles of the ovary.[18]

Animal studies

Reproductive tissue

Estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[19][20] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[19] This indicates that although GPER and ERβ play a modulatory role in breast development, ERα is the main receptor responsible for estrogen-mediated breast tissue growth.[19] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[21][22][23][24] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[24]

Cardiovascular effects

GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol.[25] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[26][27] and is required for superoxide-mediated cardiovascular function and aging.[28]

Central nervous system activity

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[29][30][31] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[32] There is a high expression of GPER, as well as ERβ, in oxytocin neurons in various parts of the hypothalamus, including the paraventricular nucleus and the supraoptic nucleus.[31][33] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[31][33] for instance, rapidly increasing oxytocin receptor expression.[34] Estradiol has also been found to increase oxytocin levels and release in the medial preoptic area and medial basal hypothalamus, actions that may be mediated by activation of GPER and/or ERβ.[34] Estradiol, as well as tamoxifen and fulvestrant, have been found to rapidly induce lordosis through activation of GPER in the arcuate nucleus of the hypothalamus of female rats.[35][36]

Metabolic roles

Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[37] Male GPER knockout mice are observed to have increased growth, body fat, insulin resistance and glucose intolerance, dyslipidemia, increased osteoblast function (mineralization), resulting in higher bone mineral density and trabecular bone volume, and persistent growth plate activity resulting in longer bones.[38][39] The GPER-selective agonist G-1 shows therapeutic efficacy in mouse models of obesity and diabetes.[40]

Role in cancer

Immunohistochemical and transcriptomic analyses of neoplasms derived from a variety of tissues including but not limited to: breast,[41][42][43][44][45][46] endometrial,[47] ovarian,[48] and testicular [49] directly link GPER to advanced disease and prometastatic growth and survival. Experimental data also strong supports a pro-oncogenic role for GPER. First, GPER is required for the survival of tumor-initiating “stem” cells derived from patient-derived tumor xenografts (PDXs).[50] Secondly, less aggressive disease occurs upon the somatic cell silencing of GPER in a robust model of PyMT-induced breast carcinogenesis.[51] Additionally, GPER-selective ligands show efficacy in nonclinical and clinical settings. For example, the GPER antagonist, G36, delays the estrogen-dependent outgrowth of transplanted endometrial carcinoma in mice,[52] while the GPER agonist, G1, has been shown to attenuate the growth of patient-derived xenografts of pancreatic ductal adenocarcinoma.[53]

A contrary argument that GPER may be tumor suppressive has been hypothesized.[54][55] However, it is important to note that Linnaeus Therapeutics is currently running NCI clinical trial (NCT04130516) using GPER agonist. LNS8801, as monotherapy or in the combination with the checkpoint inhibitor, pembroluzimab, for the treatment of multiple solid tumor malignancies.

Role in neurological disorders

GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.[56] A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.[47]

See also

References

  1. ↑ "Discovery of three novel G-protein-coupled receptor genes". Genomics 47 (2): 310–3. Jan 1998. doi:10.1006/geno.1998.5095. PMID 9479505. 
  2. ↑ 2.0 2.1 2.2 2.3 "International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators". Pharmacol. Rev. 67 (3): 505–40. July 2015. doi:10.1124/pr.114.009712. PMID 26023144. 
  3. ↑ "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology 74: 1–11. 2012. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507. 
  4. ↑ 4.0 4.1 "The many faces of estrogen signaling". Biochemia Medica 24 (3): 329–42. 2014. doi:10.11613/BM.2014.035. PMID 25351351. 
  5. ↑ 5.0 5.1 5.2 "A transmembrane intracellular estrogen receptor mediates rapid cell signaling". Science 307 (5715): 1625–30. March 2005. doi:10.1126/science.1106943. PMID 15705806. Bibcode: 2005Sci...307.1625R. 
  6. ↑ "GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release". Trends in Endocrinology and Metabolism 16 (8): 362–7. October 2005. doi:10.1016/j.tem.2005.08.005. PMID 16125968. 
  7. ↑ "Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin". Journal of Cellular Physiology 207 (3): 594–604. June 2006. doi:10.1002/jcp.20551. PMID 16270355. 
  8. ↑ "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology 265-266: 138–42. February 2007. doi:10.1016/j.mce.2006.12.010. PMID 17222505. 
  9. ↑ "Nongenomic actions of aldosterone and progesterone revisited". Steroids 77 (10): 1002–6. August 2012. doi:10.1016/j.steroids.2011.12.023. PMID 22285849. 
  10. ↑ "Anatomical location and redistribution of G protein-coupled estrogen receptor-1 during the estrus cycle in mouse kidney and specific binding to estrogens but not aldosterone". Molecular and Cellular Endocrinology 382 (2): 950–9. February 2014. doi:10.1016/j.mce.2013.11.005. PMID 24239983. 
  11. ↑ "Niacin activates the G protein estrogen receptor (GPER)-mediated signalling". Cell. Signal. 26 (7): 1466–1475. July 2014. doi:10.1016/j.cellsig.2014.03.011. PMID 24662263. "Nicotinic acid, also known as niacin, is the water soluble vitamin B3 used for decades for the treatment of dyslipidemic diseases. Its action is mainly mediated by the G protein-coupled receptor (GPR) 109A; however, certain regulatory effects on lipid levels occur in a GPR109A-independent manner. The amide form of nicotinic acid, named nicotinamide, acts as a vitamin although neither activates the GPR109A nor exhibits the pharmacological properties of nicotinic acid. In the present study, we demonstrate for the first time that nicotinic acid and nicotinamide bind to and activate the GPER-mediated signalling in breast cancer cells and cancer-associated fibroblasts (CAFs)". 
  12. ↑ "Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER". Steroids 111: 37–45. February 2016. doi:10.1016/j.steroids.2016.02.016. PMID 26921679. 
  13. ↑ "Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells". J. Cell. Physiol. 225 (3): 792–800. November 2010. doi:10.1002/jcp.22284. PMID 20568229. 
  14. ↑ "Virtual and biomolecular screening converge on a selective agonist for GPR30". Nature Chemical Biology 2 (4): 207–12. April 2006. doi:10.1038/nchembio775. PMID 16520733. 
  15. ↑ "In vivo effects of a GPR30 antagonist". Nature Chemical Biology 5 (6): 421–7. June 2009. doi:10.1038/nchembio.168. PMID 19430488. 
  16. ↑ "Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity". The Journal of Steroid Biochemistry and Molecular Biology 127 (3–5): 358–66. November 2011. doi:10.1016/j.jsbmb.2011.07.002. PMID 21782022. 
  17. ↑ "Entrez Gene: GPR30 G protein-coupled receptor 30". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2852. 
  18. ↑ "Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues". The Journal of Endocrinology 202 (2): 223–36. August 2009. doi:10.1677/JOE-09-0066. PMID 19420011. 
  19. ↑ 19.0 19.1 19.2 "GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast". Horm Cancer 5 (3): 146–60. 2014. doi:10.1007/s12672-014-0174-1. PMID 24718936. 
  20. ↑ "GPER Function in Breast Cancer: An Overview". Frontiers in Endocrinology 5: 66. 2014. doi:10.3389/fendo.2014.00066. PMID 24834064. 
  21. ↑ "Estrogens: new players in spermatogenesis". Reprod Biol 11 (3): 174–93. 2011. doi:10.1016/s1642-431x(12)60065-5. PMID 22139333. 
  22. ↑ "Estrogen signaling in testicular cells". Life Sci. 89 (15–16): 584–7. 2011. doi:10.1016/j.lfs.2011.06.004. PMID 21703280. 
  23. ↑ "Estrogen, a female hormone involved in spermatogenesis". Adv Med Sci 57 (1): 31–6. 2012. doi:10.2478/v10039-012-0005-y. PMID 22440937. 
  24. ↑ 24.0 24.1 "Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis". Front Endocrinol (Lausanne) 5: 1. 2014. doi:10.3389/fendo.2014.00001. PMID 24474947. 
  25. ↑ "Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction". Hypertension 59 (2): 507–12. February 2012. doi:10.1161/HYPERTENSIONAHA.111.184606. PMID 22203741. "The development of the GPER-selective agonist G-114 has facilitated studies that demonstrate GPER activation induces acute vasodilation and lowers blood pressure in rodents. We18 and others17,19 have shown that acute GPER-mediated vasodilator effects are at least partly endothelium- and NO-dependent.". 
  26. ↑ "Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen". Gender Medicine 8 (6): 343–54. December 2011. doi:10.1016/j.genm.2011.10.004. PMID 22153880. 
  27. ↑ "GPER: a novel target for non-genomic estrogen action in the cardiovascular system". Pharmacological Research 71: 53–60. May 2013. doi:10.1016/j.phrs.2013.02.008. PMID 23466742. 
  28. ↑ "Obligatory role for GPER in cardiovascular aging and disease". Science Signaling 9 (452): ra105. November 2016. doi:10.1126/scisignal.aag0240. PMID 27803283. 
  29. ↑ "Antidepressant effects of estrogens: a basic approximation". Behav Pharmacol 21 (5–6): 451–64. 2010. doi:10.1097/FBP.0b013e32833db7e9. PMID 20700047. 
  30. ↑ "In vivo effects of a GPR30 antagonist". Nat. Chem. Biol. 5 (6): 421–7. 2009. doi:10.1038/nchembio.168. PMID 19430488. 
  31. ↑ 31.0 31.1 31.2 "Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus". Neuroscience 158 (4): 1599–607. 2009. doi:10.1016/j.neuroscience.2008.11.028. PMID 19095043. 
  32. ↑ "Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol". Psychopharmacology 221 (3): 527–35. 2012. doi:10.1007/s00213-011-2599-3. PMID 22143579. 
  33. ↑ 33.0 33.1 Choleris, Elena (11 April 2013). Oxytocin, Vasopressin and Related Peptides in the Regulation of Behavior. Cambridge University Press. pp. 10–. ISBN 978-0-521-19035-0. https://books.google.com/books?id=8ZasDMxSI0UC&pg=PA10. 
  34. ↑ 34.0 34.1 Blaustein, Jeffrey D. (8 December 2006). Handbook of Neurochemistry and Molecular Neurobiology: Behavioral Neurochemistry, Neuroendocrinology and Molecular Neurobiology. Springer Science & Business Media. pp. 165–. ISBN 978-0-387-30362-8. https://books.google.com/books?id=ez6A_UUDHVkC&pg=PA165. 
  35. ↑ "17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats". Hormones and Behavior 66 (4): 663–6. September 2014. doi:10.1016/j.yhbeh.2014.09.008. PMID 25245158. 
  36. ↑ "Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats". Hormones and Behavior 89: 98–103. March 2017. doi:10.1016/j.yhbeh.2016.12.013. PMID 28063803. 
  37. ↑ "Deletion of the G protein-coupled Receptor GPR30 Impairs Glucose Tolerance, Reduces Bone Growth, Increases Blood Pressure, and Eliminates Estradiol-stimulated Insulin Release in Female Mice". Endocrinology 150 (2): 687–98. 2008. doi:10.1210/en.2008-0623. PMID 18845638. 
  38. ↑ "GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice". J Bone Miner Res 26 (2): 298–307. August 2010. doi:10.1002/jbmr.209. PMID 20734455. 
  39. ↑ "GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state". Endocrinology 154 (11): 4136–45. November 2013. doi:10.1210/en.2013-1357. PMID 23970785. 
  40. ↑ "Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes". Science Translational Medicine 12 (528): eaau5956. January 2020. doi:10.1126/scitranslmed.aau5956. PMID 31996464. 
  41. ↑ Filardo, Edward J.; Graeber, Carl T.; Quinn, Jeffrey A.; Resnick, Murray B.; Giri, Dilip; DeLellis, Ronald A.; Steinhoff, Margaret M.; Sabo, Edmond (2006-11-01). "Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression". Clinical Cancer Research 12 (21): 6359–6366. doi:10.1158/1078-0432.CCR-06-0860. ISSN 1078-0432. PMID 17085646. https://pubmed.ncbi.nlm.nih.gov/17085646/. 
  42. ↑ Arias-Pulido, Hugo; Royce, Melanie; Gong, Yun; Joste, Nancy; Lomo, Lesley; Lee, Sang-Joon; Chaher, Nabila; Verschraegen, Claire et al. (August 2010). "GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer". Breast Cancer Research and Treatment 123 (1): 51–58. doi:10.1007/s10549-009-0631-7. ISSN 1573-7217. PMID 19902352. 
  43. ↑ Ignatov, Atanas; Ignatov, Tanja; Weissenborn, Christine; Eggemann, Holm; Bischoff, Joachim; Semczuk, Andrzej; Roessner, Albert; Costa, Serban Dan et al. (July 2011). "G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer". Breast Cancer Research and Treatment 128 (2): 457–466. doi:10.1007/s10549-011-1584-1. ISSN 1573-7217. PMID 21607586. https://pubmed.ncbi.nlm.nih.gov/21607586/. 
  44. ↑ Sjöström, Martin; Hartman, Linda; Grabau, Dorthe; Fornander, Tommy; Malmström, Per; Nordenskjöld, Bo; Sgroi, Dennis C.; Skoog, Lambert et al. (May 2014). "Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer". Breast Cancer Research and Treatment 145 (1): 61–71. doi:10.1007/s10549-014-2936-4. ISSN 1573-7217. PMID 24715381. https://pubmed.ncbi.nlm.nih.gov/24715381/. 
  45. ↑ Talia, Marianna; De Francesco, Ernestina Marianna; Rigiracciolo, Damiano Cosimo; Muoio, Maria Grazia; Muglia, Lucia; Belfiore, Antonino; Maggiolini, Marcello; Sims, Andrew H. et al. (2020-03-04). "The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis". Cells 9 (3): 622. doi:10.3390/cells9030622. ISSN 2073-4409. PMID 32143514. 
  46. ↑ Xu, Ting; Ma, Ding; Chen, Sheng; Tang, Rui; Yang, Jianling; Meng, Chunhui; Feng, Yang; Liu, Li et al. (2022-08-30). "High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes". npj Breast Cancer 8 (1): 100. doi:10.1038/s41523-022-00472-4. ISSN 2374-4677. PMID 36042244. 
  47. ↑ 47.0 47.1 Sahin, Nilfer; Altun, Hatice; Kurutaş, Ergül Belge; Fındıklı, Ebru (2018-05-20). "Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD)". Bosnian Journal of Basic Medical Sciences 18 (2): 126–131. doi:10.17305/bjbms.2018.2942. ISSN 1840-4812. PMID 29659348. 
  48. ↑ Smith, Harriet O.; Arias-Pulido, Hugo; Kuo, Dennis Y.; Howard, Tamara; Qualls, Clifford R.; Lee, Sang-Joon; Verschraegen, Claire F.; Hathaway, Helen J. et al. (September 2009). "GPR30 predicts poor survival for ovarian cancer". Gynecologic Oncology 114 (3): 465–471. doi:10.1016/j.ygyno.2009.05.015. ISSN 1095-6859. PMID 19501895. 
  49. ↑ Chevalier, Nicolas; Vega, Aurélie; Bouskine, Adil; Siddeek, Bénazir; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick (2012). "GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation". PLOS ONE 7 (4): e34672. doi:10.1371/journal.pone.0034672. ISSN 1932-6203. PMID 22496838. Bibcode: 2012PLoSO...734672C. 
  50. ↑ Chan, Yu-Tzu; Lai, Alan C.-Y.; Lin, Ruey-Jen; Wang, Ya-Hui; Wang, Yi-Ting; Chang, Wen-Wei; Wu, Hsin-Yi; Lin, Yu-Ju et al. (2020-03-15). "GPER-induced signaling is essential for the survival of breast cancer stem cells". International Journal of Cancer 146 (6): 1674–1685. doi:10.1002/ijc.32588. ISSN 1097-0215. PMID 31340060. 
  51. ↑ Marjon, Nicole A.; Hu, Chelin; Hathaway, Helen J.; Prossnitz, Eric R. (November 2014). "G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis". Molecular Cancer Research: MCR 12 (11): 1644–1654. doi:10.1158/1541-7786.MCR-14-0128-T. ISSN 1557-3125. PMID 25030371. 
  52. ↑ Petrie, Whitney K.; Dennis, Megan K.; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R. (2013). "G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth". Obstetrics and Gynecology International 2013: 472720. doi:10.1155/2013/472720. ISSN 1687-9589. PMID 24379833. 
  53. ↑ Natale, Christopher A.; Li, Jinyang; Pitarresi, Jason R.; Norgard, Robert J.; Dentchev, Tzvete; Capell, Brian C.; Seykora, John T.; Stanger, Ben Z. et al. (2020). "Pharmacologic Activation of the G Protein-Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma". Cellular and Molecular Gastroenterology and Hepatology 10 (4): 868–880.e1. doi:10.1016/j.jcmgh.2020.04.016. ISSN 2352-345X. PMID 32376419. 
  54. ↑ Weißenborn, Christine; Ignatov, Tanja; Ochel, Hans-Joachim; Costa, Serban Dan; Zenclussen, Ana Claudia; Ignatova, Zoya; Ignatov, Atanas (May 2014). "GPER functions as a tumor suppressor in triple-negative breast cancer cells". Journal of Cancer Research and Clinical Oncology 140 (5): 713–723. doi:10.1007/s00432-014-1620-8. ISSN 1432-1335. PMID 24553912. https://pubmed.ncbi.nlm.nih.gov/24553912/. 
  55. ↑ Liu, Qiao; Chen, Zhuojia; Jiang, Guanmin; Zhou, Yan; Yang, Xiangling; Huang, Hongbin; Liu, Huanliang; Du, Jun et al. (2017-05-05). "Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer". Molecular Cancer 16 (1): 87. doi:10.1186/s12943-017-0654-3. ISSN 1476-4598. PMID 28476123. 
  56. ↑ Roque, C.; Mendes-Oliveira, J.; Duarte-Chendo, C.; Baltazar, G. (October 2019). "The role of G protein-coupled estrogen receptor 1 on neurological disorders". Frontiers in Neuroendocrinology 55: 100786. doi:10.1016/j.yfrne.2019.100786. ISSN 1095-6808. PMID 31513775. https://pubmed.ncbi.nlm.nih.gov/31513775/. 

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