REVIEW article
Front. Oncol.
Sec. Molecular and Cellular Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1513225
This article is part of the Research TopicNational Cancer Research Month 2025: Advances in Detection, Treatment and Therapies in OncologyView all 3 articles
Decoding Estrogen Receptor and GPER Biology: Structural Insights and Therapeutic Advances in ERa-positive Breast Cancer
Provisionally accepted- University of Saskatchewan, Saskatoon, Canada
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Classical estrogen receptors, ERa and ERb, along with the membrane-bound G-protein-coupled estrogen receptor (GPER), play critical roles in driving ERa-positive breast cancer (BC). Clinical management of this subtype relies on endocrine therapy (ET), which targets ER signaling through selective estrogen receptors modulators (SERMs), degraders (SERDs), and aromatase inhibitors (AIs).While ET has significantly reduced recurrence and mortality rates, acquired resistance remains a major therapeutic challenge. Activating ESR1 mutations, which encode constitutively active ERa variants, are detected in 30-50% of therapy-resistant metastatic ERa-positive BC and serve as emerging biomarkers of poor prognosis. These hot-spot mutations stabilize ERa in its agonist conformation, thereby enabling ligand-independent transcriptional activation. Understanding the conformational constraints that keep wild-type ERa in an "off-state" in the absence of ligand-and how activating ESR1 mutations disrupt these regulatory mechanisms-is critical for developing effective targeted therapies. Concurrently, GPER-mediated non-genomic signaling, often inadvertently activated by SERMs and SERDs, contributes to tamoxifen resistance. This review explores the structural and functional intricacies of ERa, the impact of ESR1 mutations on its ligand-binding domain (ERa-LBD) and their contribution to ET resistance, and the role of GPER-mediated signaling in ERa-positive BC. We further highlight recent advances in next-generation therapeutics targeting both ERa mutants and GPER, which may offer a more effective, integrated strategy to overcome ET resistance.
Keywords: breast cancer, estrogen signaling, Era, GPER, Endocrine resistance, SERM, SERD
Received: 18 Oct 2024; Accepted: 26 May 2025.
Copyright: © 2025 Saha and Lukong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Taniya Saha, University of Saskatchewan, Saskatoon, Canada
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.