Date Published: May 8, 2019
Publisher: Public Library of Science
Author(s): Gieira S. Jones, Heather Spencer Feigelson, Roni T. Falk, Xing Hua, Jacques Ravel, Guoqin Yu, Roberto Flores, Mitchell H. Gail, Jianxin Shi, Xia Xu, James J. Goedert, Alexander V. Alekseyenko.
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.
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).
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.
Mammographic density was not associated with the gut microbiota, but it was inversely associated with urinary estrogen levels.
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.
Mammographic density is a metric used to describe the amount of adipose tissue relative to the amount of connective, lobular, and ductal tissue in the breast. High mammographic density is a strong risk factor for breast cancer, but its determinants are not well established [1–5]. To further complicate the matter, how mammographic density increases breast cancer risk is unclear . Several epidemiological studies have implicated endogenous estrogen levels as a possible contributor to the breast cancer–density association [6–20]. Since estrogen functions as a mitogen that regulates breast tissue growth and development, it is biologically plausible that estrogen may mediate the relationship between mammographic density and breast cancer . However, associations of endogenous estrogen levels with mammographic density have been inconsistent, including null, positive, and inverse correlations [6,7,16–20,8–15].
Twenty-three women were classified as having low mammographic density, and 31 were classified has having high mammographic density. Participants were predominantly non-Hispanic white (86%), and nearly all (96%) had attended college, which did not differ by mammographic density status. Likewise, women with low versus high mammographic density were similar with regard to age, histories of cigarette smoking, alcohol use, vigorous/moderate physical activity, prior HRT use, breast cancer in a first-degree family member, menstruation history and parity (Table 1). Low mammographic density women had significantly higher mean BMI (P = 0.01), with 48% of low-density women being categorized as obese compared to 13% of high-density women.
Risk for postmenopausal breast cancer is substantially increased with high mammographic density, and also consistently increased with high estrogen level. Because estrogen is a mitogen that increases mammary epithelial and stromal cell growth , higher levels might mediate higher breast density. In contrast to this hypothesis, we observed that postmenopausal women with high mammographic density had significantly lower levels of estrogens and estrogen metabolites (EM) compared to women with low mammographic density. This inverse association between estrogen level and mammographic density in postmenopausal women was also found in several prior studies (S3 Table) [6–9,13–15,17] although it was greatly attenuated with adjustment for BMI, which may be an important confounding variable. In our study, the inverse association between estrogen level and mammographic density persisted after adjustment for BMI (Table 2). Moreover, the effect of BMI on estrogens appeared to be limited to a few obese women with low breast density (Fig 1). Based on limited power, the interaction of BMI and estrogen level on density was not statistically significant (P = 0.77).