Oxidative Stress May Inhibit Cancer Development in People with BRCA2 Gene Variants

Recent research from Nagoya University in Japan challenges the traditional view that oxidative stress solely promotes cancer. While oxidative stress is typically associated with increased cancer risk, a new study indicates it may actually suppress tumor formation in individuals with BRCA2 gene mutations. The team developed rat models with mutations in the Brca2 gene that mimic human hereditary cancer risk. These rats spontaneously developed malignant tumors at significantly higher rates compared to normal rats, confirming the model's relevance.

The researchers then induced oxidative stress using ferric nitrilotriacetate (Fe-NTA), a form of iron known to cause oxidative damage linked to cancer. Interestingly, in Brca2-mutant rats, initial antioxidant responses dampened lipid peroxidation and cell death. However, over time, oxidative stress caused mitochondria damage and increased lipid peroxidation, triggering ferroptosis—a form of iron-dependent cell death—leading to the elimination of potentially cancerous cells. This process acted as a protective mechanism, counteracting the genomic instability caused by BRCA2 deficiency.

This study provides the first experimental evidence that iron-induced oxidative stress can act as a tumor suppressor in the context of BRCA2 mutations, upending the assumption that oxidative stress is solely detrimental. The findings suggest that radiation exposure, often considered risky for BRCA2 mutation carriers, might not necessarily increase cancer risk via oxidative pathways.

The research opens avenues for further understanding how BRCA2 mutations induce cancer and explores potential new strategies for prevention and therapy that leverage ferroptosis to inhibit tumor development. The study underscores the complex role of oxidative stress in cancer biology and highlights the importance of context and cellular responses in determining its effects.