GPR116, An Adhesion G-Protein-Coupled-Receptor, Promotes Breast Cancer Metastasis

Metastasis is the main reason for death caused by breast cancer. Cancer cell motility and migration that plays important roles in tumor invasion and distant organ colonization are critical step for metastasis. G-protein-coupled receptors (GPCRs) constitute the hugest transmembrane receptors. Adhesion G-protein-coupled receptor (aGPCR), which contains adhesion domains in their extracellular region, is the second largest family in GPCRs. We hypothesized that adhesion GPCRs were potentially involved in breast cancer metastasis considering that adhesion domains may play vital roles in cell motility and migration.In this study, we identified GPR116as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116expression in poorly metastatic (MCF-7and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. At a molecular level, GPR116regulated breast cancer cell migration through the Gaq-p63RhoGEF-RhoA/Racl pathway. The biologic significance of GPR116in breast cancer is substantiated in human patient samples, where GPR116expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116is crucial for the metastasis of breast cancer and support GPR116as a potential prognostic marker and drug target against metastatic human breast cancer.