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.

Reference
Title of Original Paper: Endocrine therapy resistance of breast cancer: Important role of G protein- coupled estrogen receptor (GPER) and new therapeutic strategies

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101716

Funding Information:

1. The National Natural Science Foundation of China (No. 82160565, No. 82260565, No. 82104289)
2. The Jiangxi Province Ganpo Talent Support Program (China) (No. 20232BCJ23035)
3. The Youths Program of the Natural Science Foundation of Jiangxi Province, China (No. 20212BAB216063)
4. The Science and Technology Research Project of Jiangxi Provincial Department of Education (China) (No. GJJ2203530)
5. The Research Open Fund Project of Jiangxi Cancer Hospital (China) (No. KFJJ2023ZD01, No. KFJJ2023YB06)
6. The Shandong Provincial Health Commission of China (No. M-2022053)
7. The Science and Technology Innovation Plan from Weifang Medical University (Shandong, China) (No. 041004)
8. The Yuandu Scholar Grant of Weifang City, Weifang Science and Technology Bureau Plan Project (Shandong, China) (No. 2021YX081)
9. The Science and technology project jointly established by the Science and Technology Department of the State Administration of Traditional Chinese Medicine (China) (No. GZY-KJS-SD-2023-079)
10. The Shandong Provincial Medical Association Young Talent Promotion Project (China) (No. 2023_GJ_0039)
11. The Science and Technology Innovation Plan from Weifang Medical University (Shandong, China) (No. 041011)
12. The US National Institutes of Health (No. CA226303, No. DE030480)
13. The Mabel Green Myers Research Endowment Fund
14. The University of Chicago Orthopaedics Alumni Fund

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