Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption, and breast cancer

Ulla A. Hvidtfeldt, Marc J. Gunter, Theis Lange, Rowan T. Chlebowski, Dorothy Lane, Ghada N. Farhat, Matthew S. Freiberg, Niels Keiding, Jennifer S. Lee, Ross Prentice, Anne Tjønneland, Mara Z. Vitolins, Silvia Wassertheil-Smoller, Howard D. Strickler, Naja H. Rod

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Abstract

Background: Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship 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 (ER+) cases. Consuming 7+ 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 ER+ breast cancers. Conclusions: The relation of BMI with breast cancer was partly mediated 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 and obese postmenopausal women to reduce breast cancer risk.

Original languageEnglish (US)
Pages (from-to)1203-1212
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume21
Issue number7
DOIs
StatePublished - Jul 1 2012

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ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Hvidtfeldt, U. A., Gunter, M. J., Lange, T., Chlebowski, R. T., Lane, D., Farhat, G. N., Freiberg, M. S., Keiding, N., Lee, J. S., Prentice, R., Tjønneland, A., Vitolins, M. Z., Wassertheil-Smoller, S., Strickler, H. D., & Rod, N. H. (2012). Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption, and breast cancer. Cancer Epidemiology Biomarkers and Prevention, 21(7), 1203-1212. https://doi.org/10.1158/1055-9965.EPI-12-0310