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

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.