Research Article Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer

Background: Increased exposure to endogenous estrogen and/or insulin may partly explain the relation-ship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting. Methods: We combined data from two case–cohort studies based in the Women’s Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model. Results: A five-unit increase in body mass index (BMI) was associated with 50.0 [95 % confidence interval (CI), 23.2–76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8 % (95 % CI, 2.9–68.4) could be attributed to estradiol and 65.8 % (95 % CI, 13.6–273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95 % CI, 18.8–161.1) for BMI when restricted to estrogen receptor positive (ERþ) cases. Consuming 7þ drinks/wk compared with abstinence was associated with 164.9 (95 % CI, 45.8–284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ERþ breast cancers. Conclusions: The relation of BMIwith breast cancer was partlymediated through estradiol and, to a greater extent, through insulin. Impact: The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight andobese postmenopausalwomen to reduce breast cancer risk.Cancer Epidemiol Biomarkers Prev; 1–10. 2012 AACR