Triple-negative breast cancer (TNBC) accounts for 20% of
breast cancer in women and lacks an effective targeted
therapy. Therefore, finding common vulnerabilities in these
tumors represents an opportunity for more effective treatment. Despite the growing appreciation of
G-protein-coupled receptor (GPCR)-mediated signaling in
cancer pathogenesis, very little is known about the role GPCRs play in TNBC. Using genomic information of human
breast cancer, we have discovered that the orphan GPCR,
G-protein-coupled receptor 161 (GPR161) is overexpressed specifically in TNBC and correlates with poor prognosis. Knockdown of GPR161 impairs proliferation of human basal
breast cancer cell lines. Overexpression of GPR161 in human mammary epithelial cells increases cell proliferation, migration, intracellular accumulation of
E-cadherin, and formation of multiacinar structures in 3D culture. GPR161 forms a signaling complex with the scaffold
proteins β-
arrestin 2 and Ile Gln motif containing
GTPase Activating Protein 1, a regulator of
mammalian target of rapamycin complex 1 and
E-cadherin. Consistently, GPR161 amplified
breast tumors and cells overexpressing GPR161 activate
mammalian target of rapamycin signaling and decrease Ile Gln motif containing
GTPase Activating Protein 1 phosphorylation. Thus, we identify the orphan GPCR, GPR161, as an important regulator and a potential
drug target for TNBC.