Abstract
Recurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression.
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Data availability
The datasets analyzed during the current study are available in the Gene Expression Omnibus repository (GSE162532) and available upon request.
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Acknowledgements
We would like to thank Lisa Privette-Vinnedge and Megan Johnstone for their guidance and technical assistance.
Funding
This research was funded by NCI T32 CA117846 (SEW and JCD), F31 CA228373 (BGH and SEW), NCI R01 CA239697 (SEW and SIW), and US Department of Veterans Affairs grant 1IOBX000803 (SEW).
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The authors have made the following declarations about their contributions: Conceived and designed experiments: BGH, SVM, SIW, and SEW. Performed experiments: BGH, JCD, LHF, CL, and SVM. Analyzed data: BGH, JCD, LHF, SVM, CL, SIW, and SEW. Wrote the paper: BGH and SEW. All authors have read and agreed to the published version of the manuscript.
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Hunt, B.G., Davis, J.C., Fox, L.H. et al. RON-augmented cholesterol biosynthesis in breast cancer metastatic progression and recurrence. Oncogene 42, 1716–1727 (2023). https://doi.org/10.1038/s41388-023-02688-5
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DOI: https://doi.org/10.1038/s41388-023-02688-5