KEAP1 Genetic Polymorphisms Associate with Breast Cancer Risk and Survival Outcomes

Purpose: Defective oxidative stress response may increase cancer susceptibility. In tumors, these rescue mechanisms may cause chemo- and radioresistance impacting patient outcome. We previously showed that genetic variation in the nuclear factor erythroid 2-related factor 2 (NFE2L2) is associated with breast cancer risk and prognosis. Here we further studied this pathway by investigating Kelch-like ECH-associated protein 1 (KEAP1).

Experimental Design: Five tagging SNPs in the KEAP1 gene were genotyped in 996 breast cancer cases and 880 controls from two Finnish case-control sets. KEAP1 protein expression was studied in 373 invasive breast cancer tumors.

Results: rs34197572 genotype TT was associated with increased risk of breast cancer in the KBCP samples [P = 1.8×10(-4); OR, 7.314; confidence interval (CI), 2.185-24.478]. rs11085735 allele A was associated with lower KEAP1 protein expression (P = 0.040; OR,= 3.545) and high nuclear NRF2 expression (P = 0.009; OR, 2.445) and worse survival in all invasive cases (P = 0.023; HR, 1.634). When including treatment data, rs11085735 was associated with recurrence-free survival (RFS; P = 0.020; HR, 1.545) and breast cancer-specific survival (P = 0.016; HR, 1.683) and rs34197572 with overall survival (P = 0.045; HR, 1.304). rs11085735 associated with RFS also among tamoxifen-treated cases (P = 0.003; HR, 3.517). Among radiotherapy-treated cases, overall survival was associated with rs34197572 (P = 0.018; HR, 1.486) and rs8113472 (P = 0.025; HR, 1.455). RFS was associated with rs9676881 (P = 0.024; HR, 1.452) and rs1048290 (P = 0.020; HR, 1.468) among all invasive cases and among estrogen receptor (ER)-positive tamoxifen-treated cases (P = 0.018; HR, 2.407 and P = 0.015; HR, 2.476, respectively).

Conclusions: The present findings suggest that the investigated SNPs have effects related to oxidative stress induced by cancer treatment, supporting involvement of the NRF2/KEAP1 pathway in breast cancer susceptibility and patient outcome.