Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Role of G Protein-Coupled Estrogen Receptor in Cancer Progression

  • Jung, Joohee (College of Pharmacy, Duksung Women's University)
  • Received : 2018.10.04
  • Accepted : 2018.11.22
  • Published : 2019.07.15
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Abstract

Cancer is the leading cause of mortality worldwide. In cancer progression, sex hormones and their receptors are thought to be major factors. Many studies have reported the effects of estrogen and estrogen receptors (ERs) in cancer development and progression. Among them, G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor, has been identified as an estrogen membrane receptor unrelated to nuclear ER. The mechanism of GPER, including its biological action, function, and role, has been studied in various cancer types. In this review, we discuss the relation between GPER and estrogen or estrogen agonists/antagonists and cancer progression.

Keywords

References

  1. Klaassen, C.D., Watkins, J.B. and Casarett, L.J. (2010) Casarett & Doull's Essentials of Toxicology (2nd edition), McGraw-Hill Medical, New York.
  2. O'Dowd, B.F., Nguyen, T., Marchese, A., Cheng, R., Lynch, K.R., Heng, H.H., Kolakowski, L.F., Jr. and George, S.R. (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics, 47, 310-313. https://doi.org/10.1006/geno.1998.5095
  3. Thomas, P., Pang, Y., Filardo, E.J. and Dong, J. (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 146, 624-632. https://doi.org/10.1210/en.2004-1064
  4. Prossnitz, E.R. and Hathaway, H.J. (2015) What have we learned about GPER function in physiology and disease from knockout mice? J. Steroid Biochem. Mol. Biol., 153, 114-126. https://doi.org/10.1016/j.jsbmb.2015.06.014
  5. Lu, C.L. and Herndon, C. (2017) New roles for neuronal estrogen receptors. Neurogastroenterol. Motil., 29, doi:10.1111/nmo.13121 [Epub ahead of print].
  6. Hadjimarkou, M.M. and Vasudevan, N. (2018) GPER1/GPR30 in the brain: crosstalk with classical estrogen receptors and implications for behavior. J. Steroid Biochem. Mol. Biol., 176, 57-64. https://doi.org/10.1016/j.jsbmb.2017.04.012
  7. Olde, B. and Leeb-Lundberg, L.M. (2009) GPR30/GPER1: searching for a role in estrogen physiology. Trends Endocrinol. Metab., 20, 409-416. https://doi.org/10.1016/j.tem.2009.04.006
  8. Meyer, M.R., Prossnitz, E.R. and Barton, M. (2011) GPER/GPR30 and regulation of vascular tone and blood pressure. Immunol. Endocr. Metab. Agents Med. Chem., 11, 255-261. https://doi.org/10.2174/1871522211108040255
  9. Meyer, M.R., Prossnitz, E.R. and Barton, M. (2011) The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function. Vascul. Pharmacol., 55, 17-25. https://doi.org/10.1016/j.vph.2011.06.003
  10. Ohlsson, C. and Vandenput, L. (2009) The role of estrogens for male bone health. Eur. J. Endocrinol., 160, 883-889. https://doi.org/10.1530/EJE-09-0118
  11. Sharma, G. and Prossnitz, E.R. (2011) Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic beta-cells. Endocrinology, 152, 3030-3039. https://doi.org/10.1210/en.2011-0091
  12. Filardo, E.J. and Thomas, P. (2012) Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology, 153, 2953-2962. https://doi.org/10.1210/en.2012-1061
  13. Prossnitz, E.R. and Barton, M. (2014) Estrogen biology: new insights into GPER function and clinical opportunities. Mol. Cell. Endocrinol., 389, 71-83. https://doi.org/10.1016/j.mce.2014.02.002
  14. Prossnitz, E.R. and Barton, M. (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol., 7, 715-726. https://doi.org/10.1038/nrendo.2011.122
  15. Sharma, G. and Prossnitz, E.R. (2017) G-protein-coupled estrogen receptor (GPER) and sex-specific metabolic homeostasis. Adv. Exp. Med. Biol., 1043, 427-453. https://doi.org/10.1007/978-3-319-70178-3_20
  16. Sharma, G., Mauvais-Jarvis, F. and Prossnitz, E.R. (2018) Roles of G protein-coupled estrogen receptor GPER in metabolic regulation. J. Steroid Biochem. Mol. Biol., 176, 31-37. https://doi.org/10.1016/j.jsbmb.2017.02.012
  17. Liu, C., Liao, Y., Fan, S., Fu, X., Xiong, J., Zhou, S., Zou, M. and Wang, J. (2017) G-protein-coupled estrogen receptor antagonist G15 decreases estrogen-induced development of non-small cell lung cancer. Oncol. Res. doi: 10.3727/096504017X15035795904677 [Epub ahead of print].
  18. Meng, R., Qin, Q., Xiong, Y., Wang, Y., Zheng, J., Zhao, Y., Tao, T., Wang, Q., Liu, H., Wang, S., Jiang, W.G. and He, J. (2016) NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer. Oncotarget, 7, 54983-54997. https://doi.org/10.18632/oncotarget.10713
  19. Prossnitz, E.R. and Barton, M. (2009) Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER. Prostaglandins Other Lipid Mediat., 89, 89-97. https://doi.org/10.1016/j.prostaglandins.2009.05.001
  20. Prossnitz, E.R., Arterburn, J.B., Smith, H.O., Oprea, T.I., Sklar, L.A. and Hathaway, H.J. (2008) Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu. Rev. Physiol., 70, 165-190. https://doi.org/10.1146/annurev.physiol.70.113006.100518
  21. Ariazi, E.A., Brailoiu, E., Yerrum, S., Shupp, H.A., Slifker, M.J., Cunliffe, H.E., Black, M.A., Donato, A.L., Arterburn, J.B., Oprea, T.I., Prossnitz, E.R., Dun, N.J. and Jordan, V.C. (2010) The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res., 70, 1184-1194. https://doi.org/10.1158/0008-5472.CAN-09-3068
  22. Gu, Y., Chen, T., Lopez, E., Wu, W., Wang, X., Cao, J. and Teng, L. (2014) The therapeutic target of estrogen receptor-alpha36 in estrogen-dependent tumors. J. Transl. Med., 12, 16. https://doi.org/10.1186/1479-5876-12-16
  23. Carmeci, C., Thompson, D.A., Ring, H.Z., Francke, U. and Weigel, R.J. (1997) Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics, 45, 607-617. https://doi.org/10.1006/geno.1997.4972
  24. Vivacqua, A., De Marco, P., Santolla, M.F., Cirillo, F., Pellegrino, M., Panno, M.L., Abonante, S. and Maggiolini, M. (2015) Estrogenic gper signaling regulates mir144 expression in cancer cells and cancer-associated fibroblasts (cafs). Oncotarget, 6, 16573-16587. https://doi.org/10.18632/oncotarget.4117
  25. Yu, T., Liu, M., Luo, H., Wu, C., Tang, X., Tang, S., Hu, P., Yan, Y., Wang, Z. and Tu, G. (2014) GPER mediates enhanced cell viability and motility via non-genomic signaling induced by 17beta-estradiol in triple-negative breast cancer cells. J. Steroid Biochem. Mol. Biol., 143, 392-403. https://doi.org/10.1016/j.jsbmb.2014.05.003
  26. Girgert, R., Emons, G. and Grundker, C. (2012) Inactivation of GPR30 reduces growth of triple-negative breast cancer cells: possible application in targeted therapy. Breast Cancer Res. Treat., 134, 199-205. https://doi.org/10.1007/s10549-012-1968-x
  27. Grundker, C. and Emons, G. (2017) The role of gonadotropin-releasing hormone in cancer cell proliferation and metastasis. Front. Endocrinol. (Lausanne), 8, 187. https://doi.org/10.3389/fendo.2017.00187
  28. Georgescu, M.M., Morales, F.C., Molina, J.R. and Hayashi, Y. (2008) Roles of NHERF1/EBP50 in cancer. Curr. Mol. Med., 8, 459-468. https://doi.org/10.2174/156652408785748031
  29. Wang, Y., Peng, Z., Meng, R., Tao, T., Wang, Q., Zhao, C., Liu, H., Song, R., Zheng, J., Qin, Q. and He, J. (2017) NHERF1 inhibits proliferation of triple-negative breast cancer cells by suppressing GPER signaling. Oncol. Rep., 38, 221-228. https://doi.org/10.3892/or.2017.5649
  30. Marjon, N.A., Hu, C., Hathaway, H.J. and Prossnitz, E.R. (2014) G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis. Mol. Cancer Res., 12, 1644-1654. https://doi.org/10.1158/1541-7786.MCR-14-0128-T
  31. Girgert, R., Emons, G. and Grundker, C. (2014) Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17beta-estradiol. BMC Cancer, 14, 935. https://doi.org/10.1186/1471-2407-14-935
  32. Girgert, R., Emons, G. and Grundker, C. (2017) 17beta-estradiol-induced growth of triple-negative breast cancer cells is prevented by the reduction of GPER expression after treatment with gefitinib. Oncol. Rep., 37, 1212-1218. https://doi.org/10.3892/or.2016.5306
  33. Girgert, R., Emons, G. and Grundker, C. (2018) Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple-negative breast cancer by 17beta-estradiol. Oncol. Lett., 15, 9559-9566.
  34. Cirillo, F., Pellegrino, M., Malivindi, R., Rago, V., Avino, S., Muto, L., Dolce, V., Vivacqua, A., Rigiracciolo, D.C., De Marco, P., Sebastiani, A., Abonante, S., Nakajima, M., Lappano, R. and Maggiolini, M. (2017) GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer. Oncotarget, 8, 106608-106624. https://doi.org/10.18632/oncotarget.22541
  35. Lappano, R. and Maggiolini, M. (2018) GPER is involved in the functional liaison between breast tumor cells and cancer-associated fibroblasts (CAFs). J. Steroid Biochem. Mol. Biol., 176, 49-56. https://doi.org/10.1016/j.jsbmb.2017.02.019
  36. Rodriguez, C., Patel, A.V., Calle, E.E., Jacob, E.J. and Thun, M.J. (2001) Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA, 285, 1460-1465. https://doi.org/10.1001/jama.285.11.1460
  37. Zhu, C.X., Xiong, W., Wang, M.L., Yang, J., Shi, H.J., Chen, H.Q. and Niu, G. (2018) Nuclear G protein-coupled oestrogen receptor (GPR30) predicts poor survival in patients with ovarian cancer. J. Int. Med. Res., 46, 723-731. https://doi.org/10.1177/0300060517717625
  38. Smith, H.O., Arias-Pulido, H., Kuo, D.Y., Howard, T., Qualls, C.R., Lee, S.J., Verschraegen, C.F., Hathaway, H.J., Joste, N.E. and Prossnitz, E.R. (2009) GPR30 predicts poor survival for ovarian cancer. Gynecologic Oncology, 114, 465-471. https://doi.org/10.1016/j.ygyno.2009.05.015
  39. Liu, H., Yan, Y., Wen, H., Jiang, X., Cao, X., Zhang, G. and Liu, G. (2014) A novel estrogen receptor GPER mediates proliferation induced by 17beta-estradiol and selective GPER agonist G-1 in estrogen receptor alpha (ERalpha)-negative ovarian cancer cells. Cell Biol. Int., 38, 631-638. https://doi.org/10.1002/cbin.10243
  40. Yan, Y., Liu, H., Wen, H., Jiang, X., Cao, X., Zhang, G. and Liu, G. (2013) The novel estrogen receptor GPER regulates the migration and invasion of ovarian cancer cells. Mol. Cell. Biochem., 378, 1-7. https://doi.org/10.1007/s11010-013-1579-9
  41. Yan, Y., Jiang, X., Zhao, Y., Wen, H. and Liu, G. (2015) Role of GPER on proliferation, migration and invasion in ligand-independent manner in human ovarian cancer cell line SKOV3. Cell Biochem. Funct., 33, 552-559. https://doi.org/10.1002/cbf.3154
  42. Heublein, S., Mayr, D., Vrekoussis, T., Friese, K., Hofmann, S.S., Jeschke, U. and Lenhard, M. (2013) The G-protein coupled estrogen receptor (GPER/GPR30) is a gonadotropin receptor dependent positive prognosticator in ovarian carcinoma patients. PLoS ONE, 8, e71791. https://doi.org/10.1371/journal.pone.0071791
  43. Zhang, Q., Madden, N.E., Wong, A.S.T., Chow, B.K.C. and Lee, L.T.O. (2017) The role of endocrine G protein-coupled receptors in ovarian cancer progression. Front. Endocrinol. (Lausanne), 8, 66.
  44. Ignatov, T., Modl, S., Thulig, M., Weissenborn, C., Treeck, O., Ortmann, O., Zenclussen, A., Costa, S.D., Kalinski, T. and Ignatov, A. (2013) GPER-1 acts as a tumor suppressor in ovarian cancer. J. Ovarian Res., 6, 51. https://doi.org/10.1186/1757-2215-6-51
  45. Skrzypczak, M., Schuler, S., Lattrich, C., Ignatov, A., Ortmann, O. and Treeck, O. (2013) G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines. Steroids, 78, 1087-1091. https://doi.org/10.1016/j.steroids.2013.07.007
  46. Smith, H.O., Leslie, K.K., Singh, M., Qualls, C.R., Revankar, C.M., Joste, N.E. and Prossnitz, E.R. (2007) GPR30: a novel indicator of poor survival for endometrial carcinoma. Am. J. Obstet. Gynecol., 196, 386.e1-386.e11. https://doi.org/10.1016/j.ajog.2007.01.004
  47. Petrie, W.K., Dennis, M.K., Hu, C., Dai, D., Arterburn, J.B., Smith, H.O., Hathaway, H.J. and Prossnitz, E.R. (2013) G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth. Obstet. Gynecol. Int., 2013, 472720.
  48. Zhang, L., Li, Y., Lan, L., Liu, R., Wu, Y., Qu, Q. and Wen, K. (2016) Tamoxifen has a proliferative effect in endometrial carcinoma mediated via the GPER/EGFR/ERK/cyclin D1 pathway: a retrospective study and an in vitro study. Mol. Cell. Endocrinol., 437, 51-61. https://doi.org/10.1016/j.mce.2016.08.011
  49. Zhang, H., Wang, X., Chen, Z. and Wang, W. (2015) MicroRNA-424 suppresses estradiol-induced cell proliferation via targeting GPER in endometrial cancer cells. Cell. Mol. Biol., 61, 96-101.
  50. Lu, Z., Nian, Z., Jingjing, Z., Tao, L. and Quan, L. (2017) MicroRNA-424/E2F6 feedback loop modulates cell invasion, migration and EMT in endometrial carcinoma. Oncotarget, 8, 114281-114291. https://doi.org/10.18632/oncotarget.23218
  51. Krakstad, C., Trovik, J., Wik, E., Engelsen, I.B., Werner, H.M., Birkeland, E., Raeder, M.B., Oyan, A.M., Stefansson, I.M., Kalland, K.H., Akslen, L.A. and Salvesen, H.B. (2012) Loss of GPER identifies new targets for therapy among a subgroup of ERalpha-positive endometrial cancer patients with poor outcome. Br. J. Cancer, 106, 1682-1688. https://doi.org/10.1038/bjc.2012.91
  52. Jala, V.R., Radde, B.N., Haribabu, B. and Klinge, C.M. (2012) Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer. BMC Cancer, 12, 624. https://doi.org/10.1186/1471-2407-12-624
  53. Zhang, K.S., Chen, H.Q., Chen, Y.S., Qiu, K.F., Zheng, X.B., Li, G.C., Yang, H.D. and Wen, C.J. (2014) Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway. Biomed. Pharmacother., 68, 1037-1043. https://doi.org/10.1016/j.biopha.2014.09.003
  54. Hsu, L.H., Chu, N.M. and Kao, S.H. (2017) Estrogen, estrogen receptor and lung cancer. Int. J. Mol. Sci., 18, E1713. https://doi.org/10.3390/ijms18081713
  55. Jacenik, D., Cygankiewicz, A.I. and Krajewska, W.M. (2016) The G protein-coupled estrogen receptor as a modulator of neoplastic transformation. Mol. Cell. Endocrinol., 429, 10-18. https://doi.org/10.1016/j.mce.2016.04.011
  56. Zhu, G., Huang, Y., Wu, C., Wei, D. and Shi, Y. (2016) Activation of G-protein-coupled estrogen receptor inhibits the migration of human nonsmall cell lung cancer cells via IKK-beta/NF-kappaB signals. DNA Cell Biol., 35, 434-442. https://doi.org/10.1089/dna.2016.3235
  57. Avino, S., De Marco, P., Cirillo, F., Santolla, M.F., De Francesco, E.M., Perri, M.G., Rigiracciolo, D., Dolce, V., Belfiore, A., Maggiolini, M., Lappano, R. and Vivacqua, A. (2016) Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells. Oncotarget, 7, 52710-52728. https://doi.org/10.18632/oncotarget.10348
  58. Liu, Q., Chen, Z., Jiang, G., Zhou, Y., Yang, X., Huang, H., Liu, H., Du, J. and Wang, H. (2017) Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer. Mol. Cancer, 16, 87. https://doi.org/10.1186/s12943-017-0654-3
  59. Gilligan, L.C., Gondal, A., Tang, V., Hussain, M.T., Arvaniti, A., Hewitt, A.M. and Foster, P.A. (2017) Estrone sulfate transport and steroid sulfatase activity in colorectal cancer: implications for hormone replacement therapy. Front. Pharmacol., 8, 103.
  60. Santolla, M.F., Lappano, R., De Marco, P., Pupo, M., Vivacqua, A., Sisci, D., Abonante, S., Iacopetta, D., Cappello, A.R., Dolce, V. and Maggiolini, M. (2012) G protein-coupled estrogen receptor mediates the up-regulation of fatty acid synthase induced by 17beta-estradiol in cancer cells and cancer-associated fibroblasts. J. Biol. Chem., 287, 43234-43245. https://doi.org/10.1074/jbc.M112.417303
  61. Bustos, V., Nolan, A.M., Nijhuis, A., Harvey, H., Parker, A., Poulsom, R., McBryan, J., Thomas, W., Silver, A. and Harvey, B.J. (2017) GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions. Oncotarget, 8, 84258-84275. https://doi.org/10.18632/oncotarget.20653
  62. Chimento, A., Sirianni, R., Casaburi, I., Zolea, F., Rizza, P., Avena, P., Malivindi, R., De Luca, A., Campana, C., Martire, E., Domanico, F., Fallo, F., Carpinelli, G., Cerquetti, L., Amendola, D., Stigliano, A. and Pezzi, V. (2015) GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo. Oncotarget, 6, 19190-19203. https://doi.org/10.18632/oncotarget.4241
  63. Chan, Q.K., Lam, H.M., Ng, C.F., Lee, A.Y., Chan, E.S., Ng, H.K., Ho, S.M. and Lau, K.M. (2010) Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell Death Differ., 17, 1511-1523. https://doi.org/10.1038/cdd.2010.20
  64. Pisolato, R., Lombardi, A.P., Vicente, C.M., Lucas, T.F., Lazari, M.F. and Porto, C.S. (2016) Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells. Steroids, 107, 74-86. https://doi.org/10.1016/j.steroids.2015.12.021
  65. Lau, K.M. and To, K.F. (2016) Importance of estrogenic signaling and its mediated receptors in prostate cancer. Int. J. Mol. Sci., 17, E1434. https://doi.org/10.3390/ijms17091434
  66. Lau, K.M., Ma, F.M., Xia, J.T., Chan, Q.K.Y., Ng, C.F. and To, K.F. (2017) Activation of GPR30 stimulates GTP-binding of Galphai1 protein to sustain activation of Erk1/2 in inhibition of prostate cancer cell growth and modulates metastatic properties. Exp. Cell Res., 350, 199-209. https://doi.org/10.1016/j.yexcr.2016.11.022
  67. Lam, H.M., Ouyang, B., Chen, J., Ying, J., Wang, J., Wu, C.L., Jia, L., Medvedovic, M., Vessella, R.L. and Ho, S.M. (2014) Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer. Endocr. Relat. Cancer, 21, 903-914. https://doi.org/10.1530/ERC-14-0402
  68. Jia, B., Gao, Y., Li, M., Shi, J., Peng, Y., Du, X., Klocker, H., Sampson, N., Shen, Y., Liu, M. and Zhang, J. (2016) GPR30 Promotes prostate stromal cell activation via suppression of ERalpha expression and its downstream signaling pathway. Endocrinology, 157, 3023-3035. https://doi.org/10.1210/en.2016-1035
  69. Williams, G. (2012) Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-alpha and GPER signalling. Mol. Cell. Endocrinol., 351, 269-278. https://doi.org/10.1016/j.mce.2011.12.017