Identifying Gαh-Coupled Receptor and Studying on Its Translational Application in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the population of which does not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Due to the loss of these receptors, the hormone (e.g. tamoxifen) and targeted (e.g. Herceptin) therapies are less effective to treat TNBC patients. So far, the treatment of clinical TNBC patients merely relies on the traditional chemotherapy. Several studies demonstrated that the evolution of TNBC is highly aggressive but poorly differentiated. In addition, the prognosis and survival rate of patients with TNBC are relatively unfavorable to other breast cancer types. Moreover, TNBC is highly metastatic and tends to recur after chemotherapy. Therefore, it is urgently needed to dissect the molecular mechanisms for drug-resistance and metastatic progression, thereby providing a basis of developing targeted therapies to combating TNBCs. Besides, the identification of TNBC-associated cell surface markers (e.g. receptors) is also important for developing targeted therapies against TNBCs. Previously, Gαh has been shown to interact with G protein-coupled α1B-adrenergic and oxytocin receptors and trigger the PLC-δ1-related signaling cascades. In addition, our previous reports have demonstrated that the protein-protein interaction (PPI) of Gαh with PLC-δ1 regulates the action of follicle-stimulating hormone (FSH) in testicular Sertoli cells via elevating the level of intracellular Ca2+ and inositol triphosphate (IP3). Recently, we have also reported that the increased levels of Gh serves as a poor prognostic marker and predicts an unfavorable risk for cancer metastasis in TNBC patients. Moreover, therapeutically targeting of Gαh/PLC-δ1 PPI significantly inhibits the in vitro invasion ability and in vivo lung metastatic progression, tumor growth as well, in TNBC cells. Based on these findings, this proposed study will be focused on discovering the Gαh-coupled receptor (GαhR) and estimating its related application in translational medicine for combating TNBCs. To achieve this goal, in this proposed 3-year study, we will investigate the following Specific Aims: (1) To identify the Gαh-coupled receptor (GαhR) in TNBC cells; (2) To evaluate the functional consequence of GαhR expression in the metastatic progression and tumor growth of TNBCs; (3) To discover the peptide inhibitor or neutralizing antibody for therapeutically targeting GαhR in TNBCs; (4) To estimate the anti-tumor effectiveness of GαhR inhibitors on TNBCs in vitro and in vivo. The data obtained from this proposed study will probably identify a novel GαhR that might be required for promoting metastatic progression and tumor growth in TNBCs. The identified GαhR could be a useful biomarker for predicting clinical outcomes of TNBC patients. Significantly, the effectiveness of peptide drug or neutralizing antibody against GαhR on suppressing cancer metastasis and tumor growth may provide a therapeutic value in treating TNBCs clinically.