Abstract
Pathogenic variants in BRCA2 are hereditary risks for various cancers, including breast, ovary, pancreas and prostate. Genomic instability due to insufficient homologous recombination is thought as responsible for carcinogenesis. Reportedly, endogenous or exogenous aldehydes, including formaldehyde and acetaldehyde, suppress BRCA2 function. However, molecular sequences how BRCA2 insufficiency leads to carcinogenesis remains unelucidated. To assess whether Fenton reaction-based oxidative stress is a promotional risk factor of carcinogenesis in BRCA2 haploinsufficiency, we here applied iron-induced renal carcinogenesis to a newly established rat heterozygous mutation model of Brca2 (mutant, T1942Kfs/+; MUT). Rat MUT model, despite significant increase in spontaneous malignant tumors, showed no promotional effect on renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA) in contrast to our previous study using Brca1 mutant rats. Array-based comparative genome hybridization of renal cell carcinoma in MUT revealed significant increase in the frequency of homozygous Cdkn2A deletion. Whereas acute-phase analysis of the kidney after single or 1-week Fe-NTA administration to MUT showed suppressed lipid peroxidation, consistent with ferroptosis-resistance, ferroptosis and regeneration of tubular cells were coexistent with higher cytoplasmic catalytic Fe(II) levels in the subacute phase of MUT after 3-week Fe-NTA administration. Mechanistically, mitochondrial dysfunction with excess iron, promoted by insufficient BRCA2 presumably for maintaining DNA integrity, eventually initiated ferroptotic process. In conclusion, iron-dependent oxidative stress plays double-edged roles either for cell death or proliferation in carcinogenesis and its biological consequences are distinct between BRCA2 and BRCA1 haploinsufficiency. Our results suggest that iron-catalyzed oxidative stress is not a major driving force of carcinogenesis in BRCA2 pathogenic variants.
Keywords:
BRCA2; Fe-NTA; Ferroptosis; Genome instability; Mitochondria.