Loss of Ferroptosis-suppressors Accelerates Breast Cancer Recurrence by Promoting Dormancy Exit

Deleting ferroptosis regulators PNPLA2, GOT1, or GPX4 in mice accelerates breast tumor recurrence by increasing the probability that dormant cells reenter the cell cycle.

• Why it matters: Recurrence after primary treatment often arises from dormant minimal residual disease, but how ferroptosis pathways influence dormancy exit and relapse is unclear.
• What they did: Genomic analysis of paired primary–metastatic breast cancers in the same patients showed preferential ferroptosis-pathway mutations in metastases, and an in vivo CRISPR-Cas9 screen in mice selected PNPLA2, GOT1, and GPX4 guides in late dormancy and recurrence.
• The result: In mice, PNPLA2, GOT1, or GPX4 deletion accelerated recurrence and increased dormant-cell cell-cycle reentry, while dormant cells were markedly resistant to erastin and RSL3 and showed elevated reduced-to-oxidized glutathione, with worse recurrence-free and overall survival in human patients with copy number loss of these genes.