scholarly journals G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 672
Author(s):  
Richard A. Pepermans ◽  
Geetanjali Sharma ◽  
Eric R. Prossnitz
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Inflammatory Diseases ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Obesity And Diabetes ◽  
Therapeutic Value ◽  
Health And Disease ◽  
Multiple Cells ◽  
G Protein Coupled

Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.

scholarly journals The G-protein-coupled estrogen receptor GPER in health and disease

2011 ◽  
Vol 7 (12) ◽  
pp. 715-726 ◽  
Author(s):  
Eric R. Prossnitz ◽  
Matthias Barton
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Health And Disease ◽  
G Protein Coupled

scholarly journals G-Protein Coupled Estrogen Receptor in Breast Cancer

2019 ◽  
Vol 20 (2) ◽  
pp. 306 ◽  
Author(s):  
Li-Han Hsu ◽  
Nei-Min Chu ◽  
Yung-Feng Lin ◽  
Shu-Huei Kao
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Tamoxifen Resistance ◽  
Breast Cancers ◽  
Epidermal Growth ◽  
Cancer Tissues ◽  
G Protein Coupled ◽  
Positive Breast Cancer

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

scholarly journals Berberine Inhibits MDA-MB-231 Cells as an Agonist of G Protein-Coupled Estrogen Receptor 1

2021 ◽  
Vol 22 (21) ◽  
pp. 11466
Author(s):  
Miaomiao Qi ◽  
Xiang Liu ◽  
Ying Zhou ◽  
Haoyu Wang ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Isoquinoline Alkaloid ◽  
Breast Cancers ◽  
Sequestosome 1 ◽  
Promotional Effect ◽  
G Protein Coupled ◽  
Estrogen Receptor 1

G protein-coupled estrogen receptor 1 (GPER1) is a potential therapeutic target for treating triple-negative breast cancers (TNBC). However, modulators for GPER1 that can be used to treat TNBC have not appeared. Berberine (BBR) is a bioactive isoquinoline alkaloid with high oral safety. In recent years, BBR has shown an inhibitory effect on TNBC tumors such as MDA-MB-231, but the molecular target remains unclear, which hinders related clinical research. Our work proved that BBR is a modulator of GPER1 that can inhibit cell viability, migration, and autophagy of MDA-MB-231 cells. The inhibitory effect of BBR on MDA-MB-231 cells has a dependence on estrogen levels. Although BBR promoted the proteasome, which is a major factor in the degradation of GPER1, it could still induce the protein level of GPER1. Correspondingly, the transcription of cellular communication network factor 2 (CCN2) was promoted. BBR could bind to GPER1 directly and change the secondary structure of GPER1, as in the case of 17β-estradiol (E2). In addition, BBR induced not only a high degree of co-localization of GPER1 and microtubule-associated protein 1 light chain 3 (MAP1LC3), but also the accumulation of sequestosome 1 (SQSTM1/p62) by the inhibition of the nuclear translocation of the nuclear factor-kappa B (NF-κB) subunit (RELA/p65), which indicates NF-κB inhibition and anti-cancer effects. This result proved that the promotional effect of BBR on the GPER1/NF-κB pathway was closely related to its inhibitory effect on autophagy, which may serve as a new mechanism by which to explain the inhibitory effect of BBR on MDA-MB-231 cells and expand our understanding of the function of both BBR and GPER1.

High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors

2007 ◽  
Vol 14 (3) ◽  
pp. 691-702 ◽  
Author(s):  
Didier Marot ◽  
Ivan Bieche ◽  
Chantal Aumas ◽  
Stéphanie Esselin ◽  
Céline Bouquet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
G Protein ◽  
Breast Tumors ◽  
Metastasis Suppressor ◽  
Mrna Levels ◽  
Breast Cancers ◽  
G Protein Coupled Receptor ◽  
Primary Tumors ◽  
G Protein Coupled

KiSS1 is a putative metastasis suppressor gene in melanoma and breast cancer-encoding kisspeptins, which are also described as neuroendocrine regulators of the gonadotropic axis. Negative as well as positive regulation of KiSS1 gene expression by estradiol (E2) has been reported in the hypothalamus. Estrogen receptor α (ERα level is recognized as a marker of breast cancer, raising the question of whether expression of KiSS1 and its G-protein-coupled receptor (GPR54) is down- or upregulated by estrogens in breast cancer cells. KiSS1 was found to be expressed in MDA-MB-231, MCF7, and T47D cell lines, but not in ZR75-1, L56Br, and MDA-MB-435 cells. KiSS1 mRNA levels decreased significantly in ERα-negative MDA-MB-231 cells expressing recombinant ERα. In contrast, tamoxifen (TAM) treatment of ERα-positive MCF7 and T47D cells increased KiSS1 and GPR54 levels. The clinical relevance of this negative regulation of KiSS1 and GPR54 by E2 was then studied in postmenopausal breast cancers. KiSS1 mRNA increased with the grade of the breast tumors. ERα-positive invasive primary tumors expressed sevenfold lower KiSS1 levels than ERα-negative tumors. Among ERα-positive breast tumors from postmenopausal women treated with TAM, high KiSS1 combined with high GPR54 mRNA tumoral levels was unexpectedly associated with shorter relapse-free survival (RFS) relative to tumors expressing low tumoral mRNA levels of both genes. The contradictory observation of putative metastasis inhibitor role of kisspeptins and RFS to TAM treatment suggests that evaluation of KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment.

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