Abstract 5148: ADGRG1 promotes tumorigenesis, invasion/migration, and cell-cell adhesion in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with the highest risk of metastatic recurrence and shortest survival in patients. Chemotherapy, the current standard of treatment for systemic therapy in TNBC, has suboptimal efficacy but high toxicity. Therefore, drugs directed against new targets exhibiting superior efficacy and excellent safety profiles are urgently needed in the treatment of metastasis in TNBC. Recently, adhesion G protein-coupled receptors (GPCRs) have shown an important role in various cancer processes. Traditionally, GPCRs are considered excellent drug targets. In this study, we aimed to evaluate the role of ADGRG1, an adhesion GPCR, in TNBC. ADGRG1 was highly expressed in basal/TNBC compared to luminal subtypes in the Tumor Cancer Genome Atlas (TCGA) Provisional datasets. Higher expression of ADGRG1 predicted poor recurrence-free survival in TNBC patients as determined using the Kaplan-Meier plotter. ADGRG1 gene and protein expression was higher in LM2 derivative with higher lung metastatic potential compared to parental MDA-MB-231 cells. ADGRG1 knockdown using 2 independent target-specific validated siRNAs reduced cell growth by MTT assay in both MDA-MB-231 parental and LM2 cells. ADGRG1 knockdown decreased mammosphere formation in MDA-MB-231 Parental cells but not in LM2 cells. ADGRG1 knockdown significantly inhibited invasion and migration of both Parental MDA-MB-231 cells and their LM2 derivatives in Trans-well assay. In addition, ADGRG1 knockdown significantly decreased cell-cell interaction in the VybrantTM Cell Adhesion assay in both cell types. ADGRG1 was significantly overexpressed in circulating tumor cell (CTC) clusters compared to single CTCs from the LM2 xenograft models. Overall, our results indicate pro-tumorigenic and pro-metastatic role of ADGRG1 which needs further validation in animal studies. Understanding the role of ADGRG1 in cell-cell adhesion as well as its signaling in TNBC are crucial in discovering its potential as a novel and druggable target in TNBC. Citation Format: Raksha Bhat, Noor M. Abdulkareem, Hala Yasser, Hariprasad Thangavel, Meghana V. Trivedi. ADGRG1 promotes tumorigenesis, invasion/migration, and cell-cell adhesion in triple-negative breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5148.