TY - JOUR
T1 - Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk
AU - Jung, Su Yon
AU - Ho, Gloria
AU - Rohan, Thomas
AU - Strickler, Howard
AU - Bea, Jennifer
AU - Papp, Jeanette
AU - Sobel, Eric
AU - Zhang, Zuo Feng
AU - Crandall, Carolyn
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - Purpose: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. Methods: We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Results: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by traits varied 45–50% between the strata. Conclusions: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.
AB - Purpose: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. Methods: We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Results: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by traits varied 45–50% between the strata. Conclusions: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.
KW - Breast cancer
KW - Exogenous estrogen
KW - Insulin-like growth factor-I/insulin resistance-related genetic variant
KW - Obesity
KW - Physical activity
KW - Postmenopausal women
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U2 - 10.1007/s10549-017-4272-y
DO - 10.1007/s10549-017-4272-y
M3 - Article
C2 - 28478612
AN - SCOPUS:85018758119
SN - 0167-6806
VL - 164
SP - 475
EP - 495
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -