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Background 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)-l, a related hormone, and the risk of breast cancer independent of estrogen level. Methods 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 93676 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-l, free IGF-l, 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 IBMI]) and the risk of breast cancer. All statistical tests were two-sided. Results 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 [Cl] = 1.00 to 2.13, Ptrend = .02); however, the association with insulin level varied by hormone therapy (HT) use (Pintersection = .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/m²) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m² vs 18.5 to <25 kg/m² = 2.12, 95% Cl = 1.26 to 3.58, Ptrend =.003); however, this association was attenuated by adjustment for insulin (Ptrend = .40). Conclusion 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. [ABSTRACT FROM AUTHOR]