Quantifying the role of circulating unconjugated estradiol in mediating the body mass index-breast cancer association

Catherine Schairer*, Barbara J. Fuhrman, Jennifer Boyd-Morin, Jeanine M. Genkinger, Mitchell H. Gail, Robert N. Hoover, Regina G. Ziegler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Background: Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor-positive (ER+) tumors. Higher BMI also increases estrogen production. Methods: We estimated the proportion of the BMI-ER+ breast cancer association mediated through estrogen in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER+ breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography-tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI-ER+ breast cancer association using Aalen additive hazards and Cox regression models. Results: All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m2 BMI increase on ER+ breast cancer risk was mediated through unconjugated estradiol. The BMI-breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. Conclusion: Circulating unconjugated estradiol levels partially mediate the BMI-breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. Impact: Further research is required to identify mechanisms underlying the BMI-breast cancer association.

Original languageEnglish
Pages (from-to)105-113
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Issue number1
StatePublished - Jan 2016
Externally publishedYes


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