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Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women

¹ Albert Einstein College of Medicine, Bronx, New York; ² Rutgers University, New Brunswick, New Jersey; ³ Yale University School of Medicine, New Haven, Connecticut; ⁴ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁵ MedStar Research Institute, Hyattsville, Maryland; and ⁶ Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Marc Gunter, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-3089; E-mail: mgunter{at}aecom.yu.edu.

Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women's Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)_q4–q1, 1.73; 95% confidence interval (CI), 1.16–2.57; P_trend = 0.005], waist circumference (HR_q4–q1, 1.82; 95% CI, 1.22–2.70; P_trend = 0.001), and free IGF-I (HR_q4–q1, 1.35; 95% CI, 0.92–1.98; P_trend = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05–2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I. [Cancer Res 2008;68(1):329–37]

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