The anion channel GPR89 is a novel oncogene associated with tumour specific dependency in breast cancer

Background: Identification of targetable biology in breast cancer is an unmet need, particularly for triple negative (TNBC) where patient outcome poor and there are few clinically approved targeted therapies. Here, we identify the anion channel GPR89, to be a novel oncogene relevant TNBC other subtypes. Materials Methods: We analyzed GPR89 subcellular localization using immunofluorescence, fractionation, electro-microscopy techniques. developed reporter cell lines determine pH endoplasmic reticulum (ER) used assays define ion homeostasis. siRNA- shRNA- CRISPRn- mediated gene perturbation function malignant non-malignant cells organoids. genetically engineered mouse model study effects on tumor development vivo mass spectrometry analyze associated proteomes interactome. Results: found that whilst localized Golgi apparatus cells, extends ER cells. Tumor with also displayed addiction whereas those Golgi-only expression did not. In delineating underlying this relationship, MYC activation changes from plus ER. When located ER, modulated luminal facilitated unfolded protein response, limiting otherwise deleterious fitness MYC-driven stress. Using electron microscopy, ER-side mitochondria membranes it interacts voltage dependent VDAC2 drives pro-tumor by rewiring metabolism towards glycolysis. Finally, overexpression accelerates tumorigenesis murine mammary tumors ectopic Myc, suggesting facilitates Myc-driven oncogenesis. Conclusions: The voltage-dependent co-operates Myc support tumorigenesis. Selective dependency extended revealing drug target potential selection biomarker. No conflict interest.