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

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.