Interactions between ADGRF1 (GPR110) and extracellular matrix proteins govern its effects on tumorigenesis in HER2‐positive breast cancer

Background and Purpose We and others have previously shown that ADGRF1, an adhesion G protein‐coupled receptor, is overexpressed and associated with poor survival in many cancers, including human epidermal growth factor receptor‐2 (HER2) breast cancer (BC). Also, we have reported the tumour‐promoting function of ADGRF1 using preclinical models of HER2+ BC. In this study, we investigated the effect of ADGRF1 overexpression in an orthotopic in vivo model as well as downstream signalling of ADGRF1 in HER2+ BC. Experimental Approach We utilized a doxycycline (Dox)‐induced ADGRF1 overexpression system in HER2+ BC cell lines and performed various in vitro and in vivo studies. Following ADGRF1 overexpression in the presence/absence of Matrigel, laminin‐111 or collagen‐IV, we performed the mammosphere assay to assess the tumorigenicity of breast epithelial cells, as well as cAMP/IP1 assays and RNA‐sequencing, to understand the receptor function and pharmacology. We conducted cross‐linking‐aided immunoprecipitation and mass spectrometry to confirm the physical interaction between ADGRF1 and the extracellular matrix proteins present in Matrigel. Key Results We found that ADGRF1 switched from a tumour‐promoting to tumour‐suppressive function upon interaction with laminin‐111. Interaction of ADGRF1 with laminin‐111 resulted in inhibition of Gαs coupling and STAT3 phosphorylation, induction of senescence, increase in HER2 expression, and improvement of sensitivity to anti‐HER2 drugs in HER2+ BC. Conclusions ADGRF1 switches from a tumour‐promoting to tumour‐suppressive function upon interaction with laminin‐111, leading to improvements in sensitivity to anti‐HER2 drugs. Leveraging ADGRF1 interactions with laminin‐111 may allow the design of novel therapies against ADGRF1 in HER2+ BC.