Journal Article Ahead of print
PubMed: 42624887 DOI: 10.1038/s41416-026-03565-0
Role of orphan G protein-coupled receptor GPR52 in breast cancer cell multicellular organization and collective invasion.
Br J Cancer
Authors: Sarah Z Hanif, Caleb Kutz, CheukMan Cherie Au, Ingrid Torregroza, Sailesh Palikhe, Syeda Y Jannath, Tabassum Fabiha, Bhavneet Bhinder, Michael P Washburn, Dominic Devost, Shuchen Liu, Priya Bhardwaj, Todd Evans, Xiaobo Liang, Pradeep Kumar Anand, Robert Tarran, Olivier Elemento, Lukas E Dow, John Blenis, Terence E Hébert, Kristy A Brown
Affiliations
- Weill Cornell Medicine/Rockefeller University/Memorial Sloan-Kettering Cancer Center Tri-Institutional MD-PhD Program, New York, NY, USA.
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
- University of Kansas Cancer Center, Kansas City, KS, USA.
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
- Department of Surgery, Weill Cornell Medicine, New York, NY, USA.
- Hunter College, City University of New York, New York, NY, USA.
- Columbia University Computational & Systems Biology Program, Sloan-Kettering Institute of Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
- Division of Genetic, Environmental and Inhalational Disease, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
- University of Kansas Cancer Center, Kansas City, KS, USA.
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Abstract
BACKGROUND
G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and are emerging as targets for the effective treatment of cancer. The role of orphan GPCR GPR52 in cancer has not been characterized. Low mRNA expression of GPR52 in breast tumours correlates with reduced overall survival, leading to the hypothesis that loss of GPR52 supports breast cancer progression.
METHODS
CRISPR-Cas9 was used to knock out GPR52 in the human triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. 2D and 3D in vitro studies, electron microscopy, and a zebrafish xenograft model were used to assess the morphology and behaviour of GPR52 KO cells.
RESULTS
Loss of GPR52 was associated with elevated levels of cAMP, increased cell-cell interaction in 2D cultures, more spindle-like morphology on collagen, altered 3D spheroid morphology, and increased propensity to organize and invade collectively. Zebrafish injected with GPR52 KO cells developed a greater total cancer area than control. RNA sequencing and proteomic analyses of GPR52-null cells revealed an increased cAMP signalling signature. Re-expression of GPR52 and inhibition of cAMP production rescued some GPR52 KO phenotypes.
CONCLUSIONS
GPR52 loss is a potential mechanism by which breast cancer progression may occur and supports the investigation of GPR52 agonism as a therapeutic option for breast cancer.
STATEMENT OF SIGNIFICANCE
Loss of the orphan GPCR GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumour burden in zebrafish, further expanding our understanding of mechanisms driving cancer progression and opening the door to novel therapeutic approaches.
MeSH
Cells, Gtp-Binding Proteins, Breast Neoplasms, Receptors, G-Protein-Coupled, Neoplasms, Cell Line, Breast, Therapeutics