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GPR19 Drives Cell Cycle Progression via ERK-Dependent FOXM1 Activation in p53-Mutant Breast Cancer
Jihan Qiu1, Cheng Tian1, Hanzhi Li1
1Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Frontiers in Bioscience (Landmark Edition)
|July 30, 2026
Summary
G protein-coupled receptor 19 (GPR19) drives aggressive breast cancer by activating the ERK-FOXM1 pathway, making it a biomarker and therapeutic target, especially in TP53-mutant and triple-negative breast cancer (TNBC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- G protein-coupled receptor 19 (GPR19) is an orphan receptor with increasing relevance in cancer.
- Its role in breast cancer, particularly in aggressive forms with tumor protein p53 (TP53) mutations like triple-negative breast cancer (TNBC), is not well understood.
Purpose of the Study:
- Investigate the clinical significance, biological function, and molecular mechanism of GPR19 in TP53-mutant breast cancer.
- Determine if GPR19 could serve as a biomarker or therapeutic target in aggressive breast cancer subtypes.
Main Methods:
- Analyzed public datasets (GEO, TCGA) for GPR19 expression and correlation with TP53 status, subtype, and prognosis.
- Validated expression in cell lines and tissues using qPCR, Western blotting, immunofluorescence, and immunohistochemistry.
- Utilized GPR19 knockdown models, RNA sequencing, ERK activator rescue experiments, and xenograft models to elucidate the mechanism.
Main Results:
- GPR19 was significantly upregulated in TP53-mutant breast cancer, primary tumors, and TNBC, correlating with poor survival.
- GPR19 depletion inhibited proliferation, induced G2/M arrest and apoptosis in TP53-mutant cells.
- GPR19 knockdown reduced ERK phosphorylation and downstream FOXM1, CCNB1, and PLK1, while ERK activation partially reversed these effects.
Conclusions:
- GPR19 acts as an oncogenic driver and biomarker in TP53-mutant and TNBC.
- GPR19 promotes cell cycle progression and inhibits apoptosis via the ERK-FOXM1 pathway.
- This pathway represents a potential therapeutic vulnerability in aggressive breast cancer.
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