image: (A) The AlphaFold protein structure of GPER from the public database (https://alphafold.com/entry/Q99527). (B) E2, the GPER-specific agonist G1, SERMs, and SERDs activate GPER, which is predominantly localized at the cell membrane or intracellularly at the endoplasmic reticulum. GPER activates several heterotrimeric G proteins, leading to the activation of SRC, which further induces the activation of MMPs, cleaves HB-EGF, and releases free HB-EGF. HB-EGF then transactivates the EGFR, which in turn activates the downstream pathways of MAPK/ERK and PI3K/AKT, inducing gene transcription (such as c-Fos, pS2, cyclin A, cyclin D1, and cyclin E) and regulating ion channels (such as Ca2+, Na+, and K+). Other G protein-activated multiple downstream cascades include the activation of AC and the production of cAMP, followed by the activation of the PKA/CREB axis. The mobilization of Ca2+ from intracellular stores activates the PLC/PKC axis. The above signalings co-regulate downstream gene expression and promote tumor growth, invasion, metastasis, and clinical drug resistance. GPER, G protein-coupled estrogen receptor; SERMs, selective ER modulators; SERDs, selective ER downregulators; MMPs, matrix metalloproteinases; HB-EGF, heparin-binding epidermal growth factor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP-response element binding protein; PLC, phospholipase C; PKC, protein kinase C.
Credit: Tenghua Yu, Chongwu He, Hui Zhang, Yi Zhu, Annie Wang, Xiaoqiang Zeng, Yanxiao Huang, Jiamin Zhong, Xingye Wu, Yi Shu, Guowei Shen, Chao Yu, Ke Zhou, Usman Zeb, Rebeka Dejenie, Yan Peng, Rex C. Haydon, Hue H. Luu, Russell R. Reid, Tong-Chuan He, Jiaming Fan, Jingjing Li
This review published in Genes & Diseases by researchers from Nanchang Medical College, The University of Chicago Medical Center, Chongqing Hospital of Traditional Chinese Medicine, Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, The Children's Hospital of Chongqing Medical University, Nanjing Medical University, Ningbo Medical Center Li Hui Li Hospital, The University of Agriculture, Peshawar, University of California, Davis and Shandong Second Medical University provides a comprehensive synthesis of evidence identifying the G protein-coupled estrogen receptor (GPER) as a key regulator of endocrine resistance in breast cancer. Unlike classical nuclear estrogen receptors, GPER mediates rapid, non-genomic estrogen signaling and activates multiple oncogenic pathways that promote tumor survival, proliferation, and therapeutic escape.
The review systematically examines how GPER contributes to resistance across a broad spectrum of endocrine-based treatments, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and combination regimens involving CDK4/6 and PI3K/AKT/mTOR inhibitors. Elevated GPER expression is consistently associated with poor therapeutic response, disease recurrence, and unfavorable clinical prognosis. Mechanistically, GPER activation stimulates downstream signaling cascades such as EGFR, MAPK/ERK, PI3K/AKT, cAMP/PKA, and calcium-dependent pathways, enabling tumor cells to maintain estrogen-responsive growth despite effective blockade of classical estrogen receptors.
Beyond tumor-intrinsic signaling, the review highlights the role of GPER in remodeling the tumor microenvironment. GPER signaling in cancer-associated fibroblasts, immune cells, adipocytes, and endothelial cells enhances epithelial–mesenchymal transition, cancer stem-like properties, angiogenesis, and immune suppression. These microenvironmental changes reinforce endocrine resistance and support metastatic dissemination, underscoring GPER’s role as a coordinator of tumor–stroma interactions.
Importantly, the authors emphasize the clinical implications of incorporating GPER into breast cancer classification and treatment strategies. Stratifying patients based on combined ER, HER2, and GPER status may improve risk prediction and guide the selection of combination therapies. The review also discusses emerging therapeutic opportunities, including GPER antagonists, PROTAC-based degraders, and rational combination strategies integrating GPER targeting with endocrine, targeted, or immunotherapies.
Despite growing evidence supporting GPER as a therapeutic target, challenges remain, including limited clinical validation, context-dependent signaling effects, and incomplete understanding of GPER interactions with other hormonal and growth factor pathways. The review calls for integrative multi-omics studies and well-designed clinical investigations to clarify these complexities.
Overall, this review positions GPER as a central molecular hub linking non-genomic estrogen signaling to endocrine therapy resistance, offering new insights into breast cancer progression and highlighting promising avenues for improving treatment durability and patient outcomes.
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