GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Abstract

Adhesion G-protein-coupled receptors (GPCR), which contain adhesion domains in their extracellular region, have been found to play important roles in cell adhesion, motility, embryonic development, and immune response. Because most adhesion molecules with adhesion domains have vital roles in cancer metastasis, we speculated that adhesion GPCRs are potentially involved in cancer metastasis. In this study, we identified GPR116 as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116 in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116 expression in poorly metastatic (MCF-7 and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116 inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. Moreover, GPR116 modulated the formation of lamellipodia and actin stress fibers in cells in a RhoA-and Rac1-dependent manner. At a molecular level, GPR116 regulated cell motility and morphology through the Gaq-p63RhoGEF-RhoA/Rac1 pathway. The biologic significance of GPR116 in breast cancer is substantiated in human patient samples, where GPR116 expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116 is crucial for the metastasis of breast cancer and support GPR116 as a potential prognostic marker and drug target against metastatic human breast cancer. Cancer Res; 73(20); 6206-18. Ó2013 AACR.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…The levels of ADGRE5 (CD97) protein correlated strongly to tumor dedifferentiation, and targeting this Adhesion GPCR might plausibly provide therapeutic benefit. Similarly, ADGRF5 (GPR116) protein levels increased in breast cancer with progression through clinical stages and was highest in tumors with distant metastases (Davies et al, 2011;Tang et al, 2013). However, as described in section VIII, the tumor-associated Adhesion GPCRs ADGRE5 (CD97), ADGRF5 (GPR116), and ADGRG1 (GPR56) are widely expressed and not restricted to a specific cell type or tissue.…”

“…However, unlike in phagocytosis and myoblast fusion, the ADGRB1 (BAI1)-ELMO/DOCK180 interaction is dispensable for the role of ADGRB1 (BAI1) in synapse development. Further, ADGRF5 (GPR116) was recently shown to engage a Ga q -p63-RhoGEF-Rho GTPase pathway (Tang et al, 2013), and ADGRE3 (GPR97) signaling is involved in Rho kinase activation (Valtcheva et al, 2013). Other examples come from planar cell polarity (PCP) signaling during embryonic development.…”

“…Expression of ADGRF5 (GPR116) is associated with progression, metastasis, and poor prognosis in breast cancer patients (Tang et al, 2013). In breast cancer cell lines, ADGRF5 (GPR116) modulates motility and morphology via the Ga q -p63RhoGEF-Rho-GTPase pathway (Tang et al, 2013).…”

“…In breast cancer cell lines, ADGRF5 (GPR116) modulates motility and morphology via the Ga q -p63RhoGEF-Rho-GTPase pathway (Tang et al, 2013).…”

Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

“…In line with this, expression of GPR56 can inhibit vascular endothelial growth factor production in melanoma cell lines, thereby inhibiting melanoma angiogenesis and growth, a process involving the serine-threonine-proline-rich region in the ECD of GPR56, which leads to a PKCa-dependent signaling cascade (Yang et al, 2011). Similarly, expression of GPR116 (ADGRF5) has been shown to promote breast cancer metastasis via activation of Ga q -p63RhoGEF-Rho GTPase pathway (Tang et al, 2013).…”