Mechanism of GPR173-Mediated Suppression of TNBC Proliferation and Metastatic Potential via GnRHR Upregulation

Triple-negative breast cancer (TNBC) lacks effective targeted therapies, underscoring the need for novel molecular targets. Gonadotropin-releasing hormone receptor (GnRHR) has been shown to suppress TNBC proliferation and metastasis. G protein-coupled receptor 173 (GPR173), known to regulate GnRHR in neuroendocrine cells, has an undefined role in TNBC. This study aimed to determine whether GPR173 modulates TNBC progression through GnRHR-mediated signaling.

GPR173 and GnRHR expression levels were analyzed in TNBC tissues and correlated with patient prognosis. In vitro, TNBC cell lines were modified to knock down or overexpress GPR173 and GnRHR. Cell proliferation, migration, invasion, and expression of dual specificity phosphatase 1 (DUSP1), phosphorylated/total protein kinase B (AKT), phosphorylated/total extracellular signal-regulated kinase (ERK), and matrix metallopeptidase 2 (MMP2) were evaluated.

GPR173 and GnRHR expression was significantly reduced in TNBC tumors compared to normal breast tissues. Low expression of either protein correlated with poorer overall survival and increased lymph node metastasis. In vitro, GPR173 knockdown promoted TNBC cell proliferation, migration, and invasion, and reduced GnRHR expression. These changes were accompanied by increased phosphorylation of AKT and ERK, and elevated MMP2 expression. Notably, the pro-proliferative, pro-migratory, and pro-invasive effects of GPR173 knockdown were reversed by rescue overexpression of GnRHR. This GnRHR overexpression was accompanied by upregulation of DUSP1, dephosphorylation of AKT and ERK, and decreased MMP2 levels.

Based on these in vitro data, GPR173 likely constrains the pro-proliferative, pro-migratory, and pro-invasive phenotypes of TNBC cells by enhancing GnRHR signaling. These findings highlight GnRHR and GPR173 as potential therapeutic targets for TNBC.