RON-augmented cholesterol biosynthesis in breast cancer metastatic progression and recurrence

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Recurrence is a major challenge in breast cancer treatment.
• The RON receptor is implicated in breast cancer metastasis and recurrence across subtypes.
• Understanding RON's role in recurrence is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of the RON receptor in breast cancer recurrence.
• To elucidate the mechanisms by which RON promotes recurrence.
• To evaluate the efficacy of RON inhibition and cholesterol biosynthesis inhibition in preventing recurrence.

Main Methods:

• Modeling breast cancer recurrence using RON-overexpressing murine cells.
• In vivo imaging and ex vivo culture of circulating tumor cells (CTCs).
• In vitro mammosphere formation assays and transcriptomic pathway enrichment analysis.
• Treatment with a RON inhibitor (BMS777607) and statins.

Main Results:

• RON inhibition (BMS777607) reduced CTC colony formation and tumor recurrence.
• RON overexpression upregulated glycolysis and cholesterol biosynthesis.
• Cholesterol biosynthesis inhibition using statins impeded metastatic progression and recurrence without affecting primary tumors.
• RON upregulates glycolysis and cholesterol biosynthesis via MAPK-c-Myc and β-catenin-SREBP2 pathways.

Conclusions:

• The RON receptor drives breast cancer recurrence by promoting glycolysis and cholesterol biosynthesis.
• Targeting RON or cholesterol biosynthesis presents a promising strategy to prevent breast cancer metastasis and recurrence.
• Dual targeting of RON and cholesterol pathways may offer enhanced therapeutic benefits.