Inverse association between estrogen receptor-α DNA methylation and breast composition in adolescent Chilean girls

Estrogen receptor-α (ER-α) is a transcriptional regulator, which mediates estrogen-dependent breast development, as well as breast tumorigenesis. The influence of epigenetic regulation of ER-α on adolescent breast composition has not been previously studied and could serve as a marker of pubertal health and susceptibility to breast cancer. We investigated the association between ER-α DNA methylation in leukocytes and breast composition in adolescent Chilean girls enrolled in the Growth and Obesity Cohort Study (GOCS) in Santiago, Chile. Breast composition (total breast volume (BV; cm³), fibroglandular volume (FGV; cm³), and percent fibroglandular volume (%FGV)) was measured at breast Tanner stage 4 (B4). ER-α promoter DNA methylation was assessed by pyrosequencing in blood samples collected at breast Tanner stages 2 (B2; n = 256) and B4 (n = 338).

After adjusting for fat percentage at breast density measurement, ER-α methylation at B2, and cellular heterogeneity, we observed an inverse association between B4 average ER-α DNA methylation and BV and FGV. Geometric mean BV was 15% lower (95% CI: - 28%, - 1%) among girls in the highest quartile of B4 ER-α methylation (6.96-23.60%) relative to the lowest (0.78-3.37%). Similarly, FGV was 19% lower (95% CI: - 33%, - 2%) among girls in the highest quartile of B4 ER-α methylation relative to the lowest. The association between ER-α methylation and breast composition was not significantly modified by body fat percentage and was not influenced by pubertal timing.

These findings suggest that the methylation profile of ER-α may modulate adolescent response to estrogen and breast composition, which may influence breast cancer risk in adulthood.