Riccardo Ferro, Alexandra Carroll, Ana M Mendes-Pereira, Virinder Reen, George Vlachogiannis, Rebeca Uceda-Castro, Dragomir Krastev, Valeria Amodeo, Stephen Pettitt, Nadja D'Uonno, Ioanna Mavrommati, Blanca Navarro, Luke Hitchen, Jennifer Trendell, Ana Stojiljkovic, Cynthia Prince, Narinder Janghra, Ioannis Roxanis, Patrycja Gazinska, Daniel Larcombe-Young, Rebecca Marlow, Stefano Annunziato, Jos Jonkers, Tejashree Rajaram Kanitkar, Amadeus Xu, Nirmesh Patel, Nalan Liv, John Alexander, Jelmar Quist, Mercedes Pardo, Theodoros I Roumeliotis, Jyoti S Choudhary, Daniel Weekes, Pierfrancesco Marra, Joanna I Loizou, Rachael Natrajan, Anita Grigoriadis, Mallur Srivatsan Madhusudhan, Syed Haider, Christopher J Lord, Andrew Tutt
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.