Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk, has impaired TGF-β signaling capability and enhances the migration and invasion of breast cancer cells. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression. In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk.

Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and healthy controls recruited by the Breast Cancer Family Registry. The samples in this multinational cohort were primarily from younger patients (average age 49.4 and 48.1 years for cases and controls, respectively, at time of interview).

Results: Using the Cockerham model, rs7034462 was found to be associated with breast cancer risk under the dominance genetic effect but, unexpectedly, there was a significant decreased association with breast cancer for this SNP under the additive genetic effect for this model.

SNPCasesControlsCockerham Model Genetic EffectOdds Ratio95% CIP
rs7034462 (n = 2,934) 1509 1425 Additive 0.60 0.38-0.93 0.020 
   Dominance 2.09 1.29-3.38 0.002 
SNPCasesControlsCockerham Model Genetic EffectOdds Ratio95% CIP
rs7034462 (n = 2,934) 1509 1425 Additive 0.60 0.38-0.93 0.020 
   Dominance 2.09 1.29-3.38 0.002 

Conclusion: rs7034462 heterozygotes have an increased risk of breast cancer but rare homozygotes have a decreased risk. This is the first evidence in humans that constitutively decreased TGFBR1-mediated TGF-β signaling is associated with breast cancer risk.

Citation Format: John C. Henegan, Lakisha Moore-Smith, Nengjun Yi, Kui Zhang, Habibul Ahsan, Alice S. Whittemore, Boris Pasche, BCFR Co-Investigators. Association between breast cancer and constitutively decreased TGFBR1 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4856. doi:10.1158/1538-7445.AM2013-4856