Title : GPER-mediated interplay in breast cancer: From endocrine resistance to metabolic reprogramming of the tumor microenvironment
Abstract:
Background: The G Protein-Coupled Estrogen Receptor (GPER) is a non-genomic estrogen receptor widely expressed in Breast Cancer (BC). Its role extends beyond simple estrogen signaling, linking drug resistance with Tumor Microenvironment (TME) remodeling.
Methods: We systematically reviewed and integrated our own experimental data, multiomics analyses, and clinical cohorts to investigate GPER expression and function in Triple- Negative Breast Cancer (TNBC) and Hormone Receptor-Positive (HR+) BC, focusing on TME components, particularly Cancer-Associated Fibroblasts (CAFs), metabolic crosstalk, and immune evasion.
Results: GPER is expressed in~60% of BC, inversely correlated with ER/PR, but positively associated with lymph node metastasis. In TNBC, GPER drives the reverse Warburg effect through CAFs via PKA/glycolytic pathways, increasing lactate/pyruvate and glutamine metabolism, which fuels tumor progression and chemotherapy resistance. Importantly, stromal GPER predicts poor immunotherapy response (mPFS 4.0 vs. 7.8 months) and correlates with CD8+ T cell exclusion, mediated by lactate- and glutamine-enriched metabolites and exosomal creatine depletion. In HR+ BC, GPER acts as an agonist target of tamoxifen and fulvestrant, initiating endocrine resistance, promoting EMT, and mediating secondary chemoresistance through ABCG2. GPER+ CAFs also enhance local estradiol synthesis (CYP19A1) and secrete HMGB1 via PI3K/AKT to induce autophagy-mediated tamoxifen resistance. Clinically, we classified HR+/HER2− subtypes by GPER/HER2 status. For therapeutic translation, we used molecular docking to screen 204 existing drugs and selected 12 candidates for GPERtargeted repurposing, while GPER agonists like LNS8801 are being developed for melanoma (opposite effect). 94
Conclusions: GPER serves as a critical bridging hub between metabolic reprogramming of CAFs, immune escape, and endocrine/chemoresistance. Targeting GPER in the TME, rather than tumor cells alone, may overcome resistance and improve outcomes. Ongoing clinical and translational studies are exploring GPER-guided subtype-specific therapies.
