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

BMC Cancer. 2013 May 1;13:219. doi: 10.1186/1471-2407-13-219.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Alleles
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Confidence Intervals
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • MAP Kinase Kinase Kinase 1 / genetics*
  • Matrix Metalloproteinase 9 / genetics*
  • NF-kappa B / genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Signal Transduction / genetics*
  • Toll-Like Receptor 9 / genetics*
  • Toll-Like Receptors / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • NF-kappa B
  • TANK protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Matrix Metalloproteinase 9