The anion channel GPR89 is a tumor-specific dependency in breast cancer
Institution: The Breast Cancer Now Research Unit, King’s College London; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Corresponding Researcher: Andrew Tutt
Data Link(s): The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium PRIDE with the dataset identifier PXD031422 (https://www.ebi.ac.uk/pride/archive/projects/PXD031422). The publicly available TCGA data were downloaded from gdac.broadinstitute.org (release 28 January 2016). All other data are provided in the manuscript or Supplementary Information. Source data for all Figures are provided in the Source Data file accompanying the manuscript. Source data are provided with this paper.
Keyword(s): Protein folding, endoplasmic reticulum, stress signalling
Summary
How cancers regulate endoplasmic reticulum (ER) pH and minimize ER stress remains unclear. Here we show that in breast cancer, these processes are governed by the anion channel GPR89. While normally localized to the Golgi, we find GPR89 is also present in the ER of tumor cells, where it collaborates with vacuolar H⁺ ATPase to regulate pH, and reduces ER stress via IRE1α-HSP47-XBP1s, ATF6 and ATP2A2 pathways. This ER localization of GPR89 drives a tumor-specific dependency, rendering breast cancer cells, but not normal tissues, dependent on this anion channel. Structural modeling and mutagenesis identify five key amino acids essential for GPR89’s ER pH regulatory function and tumor cell survival. Consistent with its cancer-specific functions, GPR89 cooperates with Myc to accelerate mammary tumorigenesis. These findings uncover how breast cancers adapt to oncogenic stress by co-opting Golgi mechanisms of pH regulation to support ER homeostasis and survival.
