GPER: An Estrogen Receptor Key in Metastasis and Tumoral Microenvironments

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Oct 14

PMID 37834441

Authors

Ana Carolina Tirado-Garibay

Elba Andrea Falcon-Ruiz

Alejandra Ochoa-Zarzosa

Joel E Lopez-Meza

Affiliations

Soon will be listed here.

Abstract

Estrogens and their role in cancer are well-studied, and some cancer types are classified in terms of their response to them. In recent years, a G protein-coupled estrogen receptor (GPER) has been described with relevance in cancer. GPER is a pleiotropic receptor with tissue-specific activity; in normal tissues, its activation is related to correct development and homeostasis, while in cancer cells, it can be pro- or anti-tumorigenic. Also, GPER replaces estrogen responsiveness in estrogen receptor alpha (ERα)-lacking cancer cell lines. One of the most outstanding activities of GPER is its role in epithelial-mesenchymal transition (EMT), which is relevant for metastasis development. In addition, the presence of this receptor in tumor microenvironment cells contributes to the phenotypic plasticity required for the dissemination and maintenance of tumors. These characteristics suggest that GPER could be a promising therapeutic target for regulating cancer development. This review focuses on the role of GPER in EMT in tumorigenic and associated cells, highlighting its role in relation to the main hallmarks of cancer and possible therapeutic options.

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References

Filardo E, Quinn J, Bland K, Frackelton Jr A . Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 2000; 14(10):1649-60. DOI: 10.1210/mend.14.10.0532. View

Ding Q, Chorazyczewski J, Gros R, Motulsky H, Limbird L, Feldman R . Correlation of functional and radioligand binding characteristics of GPER ligands confirming aldosterone as a GPER agonist. Pharmacol Res Perspect. 2022; 10(5):e00995. PMC: 9446082. DOI: 10.1002/prp2.995. View

Buoso E, Kenda M, Masi M, Linciano P, Galbiati V, Racchi M . Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells. Front Pharmacol. 2021; 12:743991. PMC: 8490885. DOI: 10.3389/fphar.2021.743991. View

Iorga A, Cunningham C, Moazeni S, Ruffenach G, Umar S, Eghbali M . The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ. 2017; 8(1):33. PMC: 5655818. DOI: 10.1186/s13293-017-0152-8. View

Notas G, Kampa M, Castanas E . G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases. Front Endocrinol (Lausanne). 2020; 11:579420. PMC: 7564022. DOI: 10.3389/fendo.2020.579420. View

Maddalon A, Masi M, Iulini M, Linciano P, Galbiati V, Marinovich M . Effects of endocrine active contaminating pesticides on RACK1 expression and immunological consequences in THP-1 cells. Environ Toxicol Pharmacol. 2022; 95:103971. DOI: 10.1016/j.etap.2022.103971. View

Holm A, Baldetorp B, Olde B, Leeb-Lundberg L, Nilsson B . The GPER1 agonist G-1 attenuates endothelial cell proliferation by inhibiting DNA synthesis and accumulating cells in the S and G2 phases of the cell cycle. J Vasc Res. 2011; 48(4):327-35. DOI: 10.1159/000322578. View

Pepermans R, Sharma G, Prossnitz E . G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives. Cells. 2021; 10(3). PMC: 8002620. DOI: 10.3390/cells10030672. View

Roque C, Mendes-Oliveira J, Duarte-Chendo C, Baltazar G . The role of G protein-coupled estrogen receptor 1 on neurological disorders. Front Neuroendocrinol. 2019; 55:100786. DOI: 10.1016/j.yfrne.2019.100786. View

10.

Pemberton K, Rosato M, Dedert C, DeLeon C, Arnatt C, Xu F . Differential Effects of the G-Protein-Coupled Estrogen Receptor (GPER) on Rat Embryonic (E18) Hippocampal and Cortical Neurons. eNeuro. 2022; 9(4). PMC: 9291730. DOI: 10.1523/ENEURO.0475-21.2022. View

11.

Chimento A, De Luca A, Nocito M, Avena P, Padula D, Zavaglia L . Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis. Cells. 2020; 9(9). PMC: 7563107. DOI: 10.3390/cells9092115. View

12.

Yang H, Wang C, Liao H, Wang Q . Activation of GPER by E2 promotes proliferation, invasion and migration of breast cancer cells by regulating the miR-124/CD151 pathway. Oncol Lett. 2021; 21(6):432. PMC: 8045164. DOI: 10.3892/ol.2021.12693. View

13.

Deng J, Wang W, Yu G, Ma X . MicroRNA‑195 inhibits epithelial‑mesenchymal transition by targeting G protein‑coupled estrogen receptor 1 in endometrial carcinoma. Mol Med Rep. 2019; 20(5):4023-4032. PMC: 6797983. DOI: 10.3892/mmr.2019.10652. View

14.

Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q . Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021; 6(1):218. PMC: 8190181. DOI: 10.1038/s41392-021-00641-0. View

15.

Welboren W, van Driel M, Janssen-Megens E, van Heeringen S, Sweep F, Span P . ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands. EMBO J. 2009; 28(10):1418-28. PMC: 2688537. DOI: 10.1038/emboj.2009.88. View

16.

Zhu C, Xiong W, Wang M, Yang J, Shi H, Chen H . Nuclear G protein-coupled oestrogen receptor (GPR30) predicts poor survival in patients with ovarian cancer. J Int Med Res. 2017; 46(2):723-731. PMC: 5971494. DOI: 10.1177/0300060517717625. View

17.

Sharma G, Prossnitz E . Targeting the G protein-coupled estrogen receptor (GPER) in obesity and diabetes. Endocr Metab Sci. 2022; 2. PMC: 8936744. DOI: 10.1016/j.endmts.2021.100080. View

18.

Rihawi K, Ricci A, Rizzo A, Brocchi S, Marasco G, Pastore L . Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications. Int J Mol Sci. 2021; 22(8). PMC: 8067563. DOI: 10.3390/ijms22083805. View

19.

Deng Y, Miki Y, Nakanishi A . Estradiol/GPER affects the integrity of mammary duct-like structures in vitro. Sci Rep. 2020; 10(1):1386. PMC: 6987193. DOI: 10.1038/s41598-020-57819-9. View

20.

Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X . Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol Ther. 2018; 19(10):858-868. PMC: 6300341. DOI: 10.1080/15384047.2018.1456599. View