The G Protein-Coupled Estrogen Receptor (GPER) - A Critical Therapeutic Target for Cancer

Sep 24, 2026

Uploaded by Grenda

Estrogens contribute to the development of multiple cancers, driven by both endogenous production and environmental exposure to xenoestrogens. Estrogen signaling occurs through intracellular ERα/ERβ and the plasma membrane receptor GPER, which collectively elicit broad transcriptional programs via enhancers such as EREs, SREs, and CREs. Breast cancer endocrine therapy has largely followed an ER-centric ER–estrogen binary framework, overlooking GPER. Emerging ER-degrading strategies still may not address GPER, which links to tumor growth, metastasis, cancer stem cell activity, and endocrine resistance, supporting GPER-targeted therapeutics as part of a more holistic treatment strategy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages27

Reading Time1 h 8 min

AccessFree to download

Abstract

1. Introduction

2. Estrogens and Their Implications in Carcinogenesis

cells Review The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer Keith A. Hall and Edward J. Filardo * Citation: Hall, K.A.; Filardo, E.J. The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer. Cells 2023, 12, 2460 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12202460 Academic Editor: Andr¡s Balla Received: 5 August 2023 Revised: 29 September 2023 Accepted: 4 October 2023 Published: 16 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Starling Biosciences, Inc., Coralville, IA 52241, USA; [keith@starlingpharmaceuticals.com](keith@starlingpharmaceuticals.com) * Correspondence: [ed@starlingpharmaceuticals.com](ed@starlingpharmaceuticals.com) Abstract: Estrogens have been implicated in the pathogenesis of various cancers, with increasing concern regarding the overall rising incidence of disease and exposure to environmental estrogens. Estrogens, both endogenous and environmental, manifest their actions through intracellular and plasma membrane receptors, named ER􀀋, ER􀀌, and GPER. Collectively, they act to promote a broad transcriptional response that is mediated through multiple regulatory enhancers, including estrogen response elements (EREs), serum response elements (SREs), and cyclic AMP response elements (CREs) . Yet, the design and rational assignment of antiestrogen therapy for breast cancer has strictly relied upon an endogenous estrogen–ER binary rubric that does not account for environmental estrogensor GPER. New endocrine therapies have focused on the development of drugs that degrade ER via ER complex destabilization or direct enzymatic ubiquitination. However, these new approaches do not broadly treat all cancer-involved receptors, including GPER. The latter is concerning since GPERis directly associated with tumor size, distant metastases, cancer stem cell activity, and endocrine resistance, indicating the importance of targeting this receptor to achieve a more complete therapeutic response. This review focuses on the critical importance and value of GPER-targeted therapeutics as part of a more holistic approach to the treatment of estrogen-driven malignancies. Keywords: GPER; ER􀀋; ER􀀌; estrogen; xenoestrogens; phytoestrogens; breast cancer; metabolic disease; endocrine therapy; antiandrogen 1. Introduction It is an honor to contribute a feature article for this issue of Cells focusing on the G protein-coupled estrogen receptor (GPER), which has been linked to metaboregulation and cancer. It has been approximately twenty years since the ﬁrst studies providing evidence that the orphan receptor, GPR30, promotes speciﬁc estrogen binding [1,2] and rapid, nongenomic estrogen signaling [2–5] were published. A large body of literature describes its mechanism of action and the physiological and pathophysiological responses associated with this receptor, and collectively, these ﬁndings led to its rechristening to its functional designation as GPER by the receptor nomenclature committee of the IUPHAR (International Union of Pharmacologists) in 2015 [6] . This review focuses on the need for a more holistic approach to endocrine therapy that considers the roles and interplay between all sources of estrogen, endogenous and environmental, and estrogen receptors, with a special focus on GPER, given its potential importance for cancer and metabolic regulation. This review is organized in three parts. Firstly, key arguments that support the broad family of estrogens as tumor promotersin multiple human malignancies are outlined. Secondly, the receptor-based mechanisms that

FAQs

What role does GPER play in estrogen-driven cancer biology?

GPER is directly associated with tumor size, distant metastases, cancer stem cell activity, and endocrine resistance, supporting it as an important therapeutic target.

Why do current endocrine therapies for breast cancer need reconsideration?

Many therapies rely on an ER-centered endogenous estrogen–ER binary model, which does not fully account for environmental estrogens and the contribution of GPER.

What signaling pathways are mediated by estrogen receptors including GPER?

Estrogen receptors promote transcriptional responses mediated through multiple regulatory enhancers, including estrogen response elements (EREs), serum response elements (SREs), and cyclic AMP response elements (CREs).

How is GPER related to earlier receptor naming and discovery?

Evidence for an orphan receptor, GPR30, supporting specific estrogen binding and rapid non-genomic signaling led to its renaming to GPER in 2015 by the receptor nomenclature committee of IUPHAR.

Sep 24, 2026

Uploaded by Grenda