Journal of the National Cancer Institute Advance Access originally published online on December 30, 2008
JNCI Journal of the National Cancer Institute 2009 101(1):48-60; doi:10.1093/jnci/djn415
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
Affiliations of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, NY (MJG, SW-S, TER, GYFH, XX, RCK, TGH, JW-R, RDB, HDS); Department of Statistics, Rutgers University, New Brunswick, NJ (DRH, JL); Division of Chronic Disease Epidemiology, Yale University School of Medicine, New Haven, CT (HY); Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (JEM); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (GLA); MedStar Research Institute, Hyattsville, MD (BVH)
Correspondence to: Marc J. Gunter, PhD, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York, NY 10461 (e-mail: mgunter{at}aecom.yu.edu).
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)-I, 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 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.
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 [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/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% CI = 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.
| CONTEXT AND CAVEATS Prior knowledge Obesity has been linked to high circulating levels of insulin and estrogen and to an increased risk of postmenopausal breast cancer. However, it is unclear whether circulating levels of insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with the risk of breast cancer independent of estrogen level. Study design A prospective case–cohort study among nondiabetic postmenopausal women enrolled in the Women's Health Initiative Observational Study (WHI-OS) to examine associations between levels of serologic factors (including insulin, total and free IGF-I, and estradiol) in fasting serum samples, baseline characteristics (including body mass index and hormone therapy use), and the risk of breast cancer. Contribution Hyperinsulinemia and high endogenous estradiol levels were independent risk factors for postmenopausal breast cancer and largely explained the association between obesity and the risk of breast cancer in postmenopausal women. Implications Interventions aimed at lowering fasting insulin levels or circulating estrogen levels may reduce the risk of breast cancer in postmenopausal women. Limitations Only baseline levels of the serologic factors were assessed. Some case subjects may have had subclinical breast cancer at WHI-OS recruitment. The observational study design does not establish a cause-and-effect association between the measured serum levels and breast cancer. From the Editors
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Manuscript received May 6, 2008; revised September 25, 2008; accepted October 14, 2008.
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