The anion channel GPR89 is a tumor-specific dependency in breast cancer.
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.
Authors
Ferro Ferro, Carroll Carroll, Mendes-Pereira Mendes-Pereira, Reen Reen, Vlachogiannis Vlachogiannis, Uceda-Castro Uceda-Castro, Krastev Krastev, Amodeo Amodeo, Pettitt Pettitt, D'Uonno D'Uonno, Mavrommati Mavrommati, Navarro Navarro, Hitchen Hitchen, Trendell Trendell, Stojiljkovic Stojiljkovic, Prince Prince, Janghra Janghra, Roxanis Roxanis, Gazinska Gazinska, Larcombe-Young Larcombe-Young, Marlow Marlow, Annunziato Annunziato, Jonkers Jonkers, Kanitkar Kanitkar, Xu Xu, Patel Patel, Liv Liv, Alexander Alexander, Quist Quist, Pardo Pardo, Roumeliotis Roumeliotis, Choudhary Choudhary, Weekes Weekes, Marra Marra, Loizou Loizou, Natrajan Natrajan, Grigoriadis Grigoriadis, Madhusudhan Madhusudhan, Haider Haider, Lord Lord, Tutt Tutt
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