Abstract A236: The orphan G-protein coupled receptor GPR161 is an oncogene in triple negative breast cancer.

Abstract

Abstract 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. Recent large-scale analyses of hundreds of tumor samples have provided a deluge of information on the genetic changes occurring during tumorigenesis. However, determining which changes drive tumor initiation and progression, and which are bystanders remains a difficult biological problem. Utilizing this genomic information we have discovered that the orphan G-protein coupled receptor (GPCR) GPR161 is overexpressed specifically in TNBC. TNBC patients expressing higher levels of GPR161 have an increased probability of disease relapse. Overexpression of GPR161 in human non-transformed mammary epithelial cells increases cell proliferation and multiacinar structure formation in three-dimensional (3D) culture through activation of mTORC1 signaling. Knockdown of GPR161 impairs proliferation of a human basal breast cancer cell line. Furthermore, GPR161 expression induces cell migration and invasion of cells in 3D culture. This is accompanied by disrupted cell adhesion and intracellular accumulation of E-cadherin. Cells overexpressing GPR161 show a reduction in IQGAP1 phosphorylation, consistent with mTOR activation and E-cadherin disruption. Furthermore, we find GPR161 in a signaling complex with the scaffold proteins β-arrestin 2 and IQGAP1. These results suggest that GPR161 may provide prognostic value and serve as a potential drug target in TNBC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A236. Citation Format: Michael E. Feigin, Bin Xue, Molly Hammell, Senthil K. Muthuswamy. The orphan G-protein coupled receptor GPR161 is an oncogene in triple negative breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A236.