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Open Access Research article

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

Alexa J Resler135*, Kathleen E Malone13, Lisa G Johnson1, Mari Malkki2, Effie W Petersdorf2, Barbara McKnight14 and Margaret M Madeleine13

Author Affiliations

1 Program in Epidemiology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA

2 Program in Immunogenetics, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA

3 Department of Epidemiology, University of Washington, Health Sciences Building, NE Pacific Street, Seattle, WA 98195, USA

4 Department of Biostatistics, University of Washington, Health Sciences Building, NE Pacific Street, Seattle, WA 98195, USA

5 Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Mail Stop M4-C308, Seattle, WA 98109, USA

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BMC Cancer 2013, 13:219  doi:10.1186/1471-2407-13-219

Published: 1 May 2013

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.

Keywords:
Breast cancer; Genetic variation; Inflammation; TLR; NFκB