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. Oncogene-driven endoplasmic reticulum (ER) stress is common in cancer. Here, authors show breast cancers extend Golgi anion channel GPR89 to the ER to mitigate this stress, creating a potentially targetable dependency and new therapeutic strategy.

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Publication Details

Journal
Nature Communications
Published
2026-08-24
DOI
https://doi.org/10.1038/s41467-026-76250-8
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
0.00

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article

The anion channel GPR89 is a tumor-specific dependency in breast cancer

Jennifer Trendell, Nadja D’Uonno, Pierfrancesco Marra, Amadeus Xu et al.
Nature Communications
Endoplasmic Reticulum Stress and Disease
article

The anion channel GPR89 is a tumor-specific dependency in breast cancer

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

Abstract

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. Oncogene-driven endoplasmic reticulum (ER) stress is common in cancer. Here, authors show breast cancers extend Golgi anion channel GPR89 to the ER to mitigate this stress, creating a potentially targetable dependency and new therapeutic strategy.

Nature Communications
Wrocław University of Science and Technology (PL), Institute of Cancer Research (GB), Indian Institute of Science Education and Research Pune (IN), King's College London (GB), Breast Cancer Now (GB), Cancer Research UK (GB), The Netherlands Cancer Institute (NL), University Medical Center Utrecht (NL), Oncode Institute (NL), Łukasiewicz Research Network – PORT Polish Center for Technology Development (PL), AGH University of Krakow (PL)
Breast Cancer Now, Francis Crick Institute, Cancer Research UK, Imperial College London, Menzies Centre for Australian Studies, King's College London, University of London
Good health and well-being
Openalex Percentile: Top 14%
Endoplasmic Reticulum Stress and Disease
DOIOpen Access PDFOpenAlex
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