Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study

Abstract

Background: Toll-like receptors (TLRs) and the transcription factor nuclear factor-κB (NFκB) are important in inflammation and cancer.

Methods: We examined the association between breast cancer risk and 233 tagging single nucleotide polymorphisms within 31 candidate genes involved in TLR or NFκB pathways. This population-based study in the Seattle area included 845 invasive breast cancer cases, diagnosed between 1997 and 1999, and 807 controls aged 65-79.

Results: Variant alleles in four genes were associated with breast cancer risk based on gene-level tests: MAP3K1, MMP9, TANK, and TLR9. These results were similar when the risk of breast cancer was examined within ductal and luminal subtypes. Subsequent exploratory pathway analyses using the GRASS algorithm found no associations for genes in TLR or NFκB pathways. Using publicly available CGEMS GWAS data to validate significant findings (N = 1,145 cases, N = 1,142 controls), rs889312 near MAP3K1 was confirmed to be associated with breast cancer risk (P = 0.04, OR 1.15, 95% CI 1.01-1.30). Further, two SNPs in TANK that were significant in our data, rs17705608 (P = 0.05) and rs7309 (P = 0.04), had similar risk estimates in the CGEMS data (rs17705608 OR 0.83, 95% CI 0.72-0.96; CGEMS OR 0.90, 95% CI 0.80-1.01 and rs7309 OR 0.83, 95% CI 0.73-0.95; CGEMS OR 0.91, 95% CI 0.81-1.02).

Conclusions: Our findings suggest plausible associations between breast cancer risk and genes in TLR or NFκB pathways. Given the few suggestive associations in our data and the compelling biologic rationale for an association between genetic variation in these pathways and breast cancer risk, further studies are warranted that examine these effects.

Figure 1

Toll-like Receptor (TLR) Signaling Pathways. Classical TLR signaling pathways that result in NFκB activation are either MyD88-dependent (A) or MyD88-independent (B). In MyD88-dependent pathways TLR signaling occurs through the IRAK4/ IRAK1 complex, while in MyD88-independent pathways TLRs signal through TICAM1. TRAF6 then signals to the IKK complex through MAP3K7, which finally leads to NFκB activation. MyD88-independent signaling pathways can also result in the activation of IRF3 or IRF7. Genes assayed by this study are bolded and italicized. This figure was adapted from the KEGG “Toll-like receptor signaling pathway” (http://www.genome.jp/kegg/pathway/hsa/hsa04620.html).