A novel role of ADGRF1 (GPR110) in promoting cellular quiescence and chemoresistance in human epidermal growth factor receptor 2‐positive breast cancer

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Abstract
While G protein‐coupled receptors (GPCRs) are known to be excellent drug targets, the second largest family of adhesion‐GPCRs is less explored for their role in health and disease. ADGRF1 (GPR110) is an adhesion‐GPCR and has an important function in neurodevelopment and cancer. Despite serving as a poor predictor of survival, ADGRF1’s coupling to G proteins and downstream pathways remain unknown in cancer. We evaluated the effects of ADGRF1 overexpression on tumorigenesis and signaling pathways using two human epidermal growth factor receptor‐2‐positive (HER2+) breast cancer (BC) cell‐line models. We also interrogated publicly available clinical datasets to determine the expression of ADGRF1 in various BC subtypes and its impact on BC‐specific survival (BCSS) and overall survival (OS) in patients. ADGRF1 overexpression in HER2+ BC cells increased secondary mammosphere formation, soft agar colony formation, and % of Aldefluor‐positive tumorigenic population in vitro and promoted tumor growth in vivo. ADGRF1 co‐immunoprecipitated with both Gαs and Gαq proteins and increased cAMP and IP1 when overexpressed. However, inhibition of only the Gαs pathway by SQ22536 reversed the pro‐tumorigenic effects of ADGRF1 overexpression. RNA‐sequencing and RPPA analysis revealed inhibition of cell cycle pathways with ADGRF1 overexpression, suggesting cellular quiescence, as also evidenced by cell cycle arrest at the G0/1 phase and resistance to chemotherapy in HER2+ BC. ADGRF1 was significantly overexpressed in the HER2‐enriched BC compared to luminal A and B subtypes and predicted worse BCSS and OS in these patients. Therefore, ADGRF1 represents a novel drug target in HER2+ BC, warranting discovery of novel ADGRF1 antagonists.
Funding Information
  • U.S. Department of War (W81XWH‐14‐1‐0340)
  • U.S. Department of War (W81XWH‐14‐1‐0341)
  • National Institutes of Health (CA125123,P50)
  • National Institutes of Health (CA058183)
  • National Institutes of Health (CA186784‐01)
  • Breast Cancer Research Foundation (BCRF‐18‐145)
  • Breast Cancer Research Foundation (19‐145)

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