Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women

Abstract

Purpose: Positive energy imbalance and growth factors linked to obesity promote the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. As the obesity–breast cancer associations differ between European American (EA) and African-American (AA) women, we investigated genetic variants in the mTOR pathway and breast cancer risk in these two racial groups. Methods: We examined 400 single-nucleotide polymorphisms (SNPs) in 31 mTOR pathway genes in the Women’s Circle of Health Study with 1263 incident breast cancers (645 EA, 618 AA) and 1382 controls (641 EA, 741 AA). Multivariable logistic regression was performed separately within racial groups. Effect modification was assessed for measured body size and weight gain since age 20. Results: In EA women, variants in FRAP1 rs12125777 (intron), PRR5L rs3740958 (synonymous coding), and CDKAL1 rs9368197 (intron) were associated with increased breast cancer risk, while variants in RPTOR rs9900506 (intron) were associated with decreased risk (nominal p-trend for functional and FRAP1 SNPs or p adjusted for correlated test [pACT] < 0.05). For AA women, variants in RPTOR rs3817293 (intron), PIK3R1 rs7713645 (intron), and CDKAL1 rs9368197 were associated with decreased breast cancer risk. The significance for FRAP1 rs12125777 and RPTOR rs9900506 in EA women did not hold after correction for multiple comparisons. The risk associated with FRAP1 rs12125777 was higher among EAs who had body mass index ≥30 kg/m2 (odds ratio = 7.69, 95 % CI 2.11–28.0; p-interaction = 0.007) and gained weight ≥35 lb since age 20 (odds ratio = 3.34, 95 % CI 1.42–7.85; p-interaction = 0.021), compared to their counterparts. Conclusions: The mTOR pathway may be involved in breast cancer carcinogenesis differently for EA and AA women.