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