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The role of the SLC25A15 transporter in the formation of liver metastasis in ESR1-mutated breast cancer

Oncogene volume 45, pages 603–619 (2026)Cite this article

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Abstract

Activating mutations in the ligand-binding domain of the estrogen receptor (ER)-encoding (ESR1) gene are present in up to 40% of metastatic breast cancer (BC) patients and are strongly associated with a high risk of liver metastasis (LM) formation. Using the MCF-7 BC model, we investigated whether the increased hepatic tropism of ESR1-mutated BC cells is driven by their metabolic adaptation to the liver microenvironment. Indeed, metabolomic analysis revealed elevated metabolites related to the urea cycle (UC) in LM-forming ESR1-mutated cells compared to wild-type (WT) ER-expressing cells, which failed to generate LM. The subsequent proteomic, western blotting, and qPCR analyses demonstrated a dramatic upregulation of the UC constituent, the mitochondrial ornithine/citrulline transporter SLC25A15, in liver-predilected ESR1-mutated cells relative to their WT counterpart cells. Unlike WT cells, ESR1-mutated cells readily formed spheroids and exhibited enhanced migration in liver mimicking hepatocyte-conditioned media. In addition, we employed a novel ex vivo approach where ESR1 mutated cells were seeded onto colonized fresh liver tissue—which was abolished by SLC25A15 knockout. Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.

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Fig. 1: ER mutations promote liver metastasis formation by BC cells.
Fig. 2: Mutated-ER BC cells display enhanced urea cycle activity and elevated levels of SLC25A15.
Fig. 3: SLC25A15 deletion inhibits mitochondrial activity and UC in the mut-ER BC cells.
Fig. 4: Targeting SLC25A15 robustly inhibits hepatic tropism of mut-ER BC cells in vitro, ex vivo and in vivo.
Fig. 5: Elevated SLC25A15 in mut-ER cells promotes BC cell adaptation to the liver microenvironment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Funding

This study was supported by the Israel Science Foundation to D.F, I.W and T.R (grant no 2861/24), and by The Dubrovsky Family Research Fund for Solid Cancers, the Cancer Biology Research Center, Tel-Aviv University to I.W and T.R.

Author information

Author notes

  1. These authors contributed equally: Marwa Taya, Daniel Fishman.

  2. These authors jointly supervised this work: Ido Wolf, Israel Sekler, Tami Rubinek.

Authors and Affiliations

  1. Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Marwa Taya, Lotem Zinger, Keren Merenbakh-Lamin, Shaked Elfasi Sosner, Anat Klein Goldberg, Galit Winkler, Ido Wolf & Tami Rubinek

  2. The Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel

    Marwa Taya, Lotem Zinger, Shaked Elfasi Sosner, Eric Shifrut, Ido Wolf & Tami Rubinek

  3. Department of Physiology, Faculty of Health Science, Ben Gurion University of the Negev, Beer-Sheva, Israel

    Daniel Fishman, Anil Khushalrao Shendge & Israel Sekler

  4. Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Fahim Kanani & Shmuel Cohen

  5. First Faculty of Medicine, Charles University, Prague, Czech Republic

    Uri Wolf

  6. George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Eric Shifrut

  7. Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Eric Shifrut

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Contributions

MT- Collected the data, performed the analysis of in vitro and in vivo assays, and wrote the manuscript. DF- Conceived the research, collected the data, and performed the analysis of in vitro assays. FK- performed in vivo experiment. IS- Conceived and contributed to the analysis. IW- Conceived and designed the analysis. TR- Conceived and designed the analysis, performed the analysis, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ido Wolf, Israel Sekler or Tami Rubinek.

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The experiments on animals were conducted in accordance with the institutional guidelines of the Sourasky Medical Center, in accordance with current regulations and standards of the institution's Animal Care and Use Committee.

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Taya, M., Fishman, D., Kanani, F. et al. The role of the SLC25A15 transporter in the formation of liver metastasis in ESR1-mutated breast cancer. Oncogene 45, 603–619 (2026). https://doi.org/10.1038/s41388-025-03640-5

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