Mammographic breast density and its association with urinary estrogens and the fecal microbiota in postmenopausal women

Abstract

Background: Breast density, as estimated by mammography, is a strong risk factor for breast cancer in pre- and postmenopausal women, but the determinants of breast density have not yet been established. The aim of this study was to assess if urinary estrogens or gut microbiota alterations are associated with mammographic density in postmenopausal women.

Methods: Among 54 cancer-free, postmenopausal controls in the Breast and Colon Health study, we classified low- versus high-density women with Breast Imaging Reporting and Data System (BI-RADS, 5th edition) mammographic screening data, then assessed associations with urinary estrogens and estrogen metabolites (determined by liquid chromatography/tandem mass spectrometry), and fecal microbiota alpha and beta diversity (using Illumina sequencing of 16S rRNA amplicons).

Results: Multiple logistic regression revealed no significant association between breast density and fecal microbiota metrics (PD_tree P-value = 0.82; un-weighted and weighted UniFrac P = 0.92 and 0.83, respectively, both by MiRKAT). In contrast, total urinary estrogens (and all 15 estrogens/estrogen metabolites) were strongly and inversely associated with breast density (P = 0.01) after adjustment for age and body mass index.

Conclusion: Mammographic density was not associated with the gut microbiota, but it was inversely associated with urinary estrogen levels.

Impact: The finding of an inverse association between urinary estrogens and breast density in cancer-free women adds to the growing breast cancer literature on understanding the relationship between endogenous estrogens and mammographic density.

Fig 1. High mammographic density (MD) associated with both lower body mass index (Kg/M², P = 0.04) and lower total estrogen level (pmol/mg creatinine, P = 0.02) among postmenopausal women.

The logistic regression model for MD included age as a covariate.

Fig 2. Box plot comparisons of microbiota relative abundance at the Phylum level among low and high mammographic density postmenopausal women.

Fig 3. Stacked Bar Chart of the 90^th Percentile of most abundant microbiota at the Genus level among high and low mammographic density postmenopausal women.

Fig 4. Box plot comparisons of beta diversity between low and high mammographic density postmenopausal women.

Boxes represent the interquartile range (IQR), central bar the median value, whiskers 1.5-times the IQR, and circles the outlier values. In the un-weighted UniFrac comparison (left panel), the first principal coordinate (PCOA1) accounted for 23% of the variance. In the weighted comparison (right panel), PCOA1 accounted for 52% of the variance.