Germline APOE ε2 homozygosity and reduced risk of breast cancer: a population-based cohort study

We evaluated whether Apolipoprotein E (APOE) ε2 homozygosity, a germline variant associated with lower LDL cholesterol, is linked to reduced risk of breast cancer. We analyzed data from 234,857 cancer-free and dementia-free women in the UK Biobank. APOE genotypes were classified as ε2 homozygotes, ε2 heterozygotes, and non-ε2 carriers. Incident breast cancer was assessed via national registry linkage. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Subgroup analyses were conducted by lifestyle, metabolic, and female-specific factors. Over a median follow-up of 12.3 years, 7,961 first primary breast cancers occurred. Compared to non-ε2 carriers, ε2 homozygotes had significantly lower breast cancer risk (HR, 0.64; 95% CI 0.45-0.90). The protective association of ε2/ε2 was stronger in participants with smoking history. APOE ε2 homozygosity was associated with reduced risk of breast cancer, particularly under inflammatory stress. These findings suggest that genetically determined lipid and inflammatory regulation may influence breast cancer susceptibility.