Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
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Open Access
- 30 December 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 101 (1), 48-60
- https://doi.org/10.1093/jnci/djn415
Abstract
The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level. We conducted a case–cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided. Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, Ptrend = .02); however, the association with insulin level varied by hormone therapy (HT) use ( Pinteraction = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, Ptrend < .001). Obesity (BMI ≥30 kg/m 2 ) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m 2 vs 18.5 to 2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend = .003); however, this association was attenuated by adjustment for insulin ( Ptrend = .40). These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity–breast cancer relationship.Keywords
This publication has 62 references indexed in Scilit:
- Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal WomenCancer Research, 2008
- Circulating Insulin-Like Growth Factor-I and Binding Protein-3 and the Risk of Breast CancerCancer Epidemiology, Biomarkers & Prevention, 2007
- Interactions between Body Mass Index and Hormone Therapy and Postmenopausal Breast Cancer Risk (United States)Cancer Causes & Control, 2006
- Serum C‐peptide levels and breast cancer risk: Results from the European prospective investigation into cancer and nutrition (EPIC)International Journal of Cancer, 2006
- Prevalence of Overweight and Obesity in the United States, 1999-2004JAMA, 2006
- Body size and breast cancer risk: Findings from the European prospective investigation into cancer and nutrition (EPIC)International Journal of Cancer, 2004
- Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysisThe Lancet, 2004
- Circulating levels of insulin‐like growth factor I, its binding proteins ‐1,‐2, ‐3, C‐peptide and risk of postmenopausal breast cancerInternational Journal of Cancer, 2003
- Serum insulin-like growth factor-I and breast cancerInternational Journal of Cancer, 2000
- Insulin Induction of Protein Kinase C Expression Is Independent of Insulin Receptor Tyr1162/1163 Residues and Involves Mitogen-Activated Protein Kinase Kinase 1 and Sustained Activation of Nuclear p44MAPKEndocrinology, 1998