title: Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption, and breast cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Social Medicine Section, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. ulah@sund.ku.dk
authors.forename: Ulla A
authors.initials: UA
authors.lastname: Hvidtfeldt
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Gunter
authors.forename: Theis
authors.initials: T
authors.lastname: Lange
authors.forename: Rowan T
authors.initials: RT
authors.lastname: Chlebowski
authors.forename: Dorothy
authors.initials: D
authors.lastname: Lane
authors.forename: Ghada N
authors.initials: GN
authors.lastname: Farhat
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Freiberg
authors.forename: Niels
authors.initials: N
authors.lastname: Keiding
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lee
authors.forename: Ross
authors.initials: R
authors.lastname: Prentice
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Mara Z
authors.initials: MZ
authors.lastname: Vitolins
authors.forename: Silvia
authors.initials: S
authors.lastname: Wassertheil-Smoller
authors.forename: Howard D
authors.initials: HD
authors.lastname: Strickler
authors.forename: Naja H
authors.initials: NH
authors.lastname: Rod
mesh_terms: D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology*; D016022:Case-Control Studies; D004967:Estrogens / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015994:Incidence; D007328:Insulin / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000209:etiology*; D011379:Prognosis; D014481:United States / Q000453:epidemiology; D016387:Women's Health
chemical_list: D004967:Estrogens; D007004:Hypoglycemic Agents; D007328:Insulin