Greater exposure to estrogen throughout a woman's lifetime increases her risk of developing breast cancer. In the gut, microflora play a significant role in the metabolism of estrogens; therefore, inter-individual differences in host bacterial populations may be a determinant of estrogen exposure and ultimately of breast cancer risk. Colonic microfloral conversion of the soy isoflavone daidzein to equol is a biomarker of a unique intestinal bacterial population. Irrespective of soy intake, women with the capacity to produce equol have hormonal profiles associated with a lower risk of breast cancer. Only about a third of individuals have the yet-to-be-identified bacteria capable of producing equol, and equol-producer status can be determined readily from a urine sample collected after a 3-day soy challenge. We postulate that women who are equol-producers have lower cumulative exposure to estrogens. We propose to examine relationships between equol-producer status and markers of cumulative estrogen exposure (breast and bone densities), selected steroid hormones and SHBG, and the 2-hydroxyestrone: 16alpha-hydroxyestrone (2-OHE1:16alpha-OHE 1) ratio. As secondary aims we will examine associations between the density and estrogen measures, and explore the impact of diet and other exposures on equol-producer phenotype. We will recruit 750 healthy, premenopausal volunteers from within Group Health Cooperative (GHC), aged 40-45 years, and who have had a screening mammogram in the past year. At GHC, mammograms are classified into categories of density according to the American College of Radiology Breast Imaging and Data Reporting System (BI-RADS). We will recruit 250 women each within BI-RADS Groups: 1 and 2 combined, 3, and 4. Data on general health, demographics, dietary intake, physical activity, reproductive history and risk factors will be collected. After a 3-day soy challenge, women will collect a first-void urine on the fourth day for analysis of equol. Each woman will be classified as an equol-producer or nonproducer. 150 of the women will also be invited for a clinic visit to have their hip and spine bone densities measured by DEXA, and to provide a blood sample for steroid hormone analysis and a spot urine for 2-OHE1 and 16alpha- OHE1 analysis. Differences in breast density, bone density, steroid hormones, SHBG, and 2-OHEI:16alpha-OHE1 by equol producer status will be examined. In addition, we will evaluate whether equol production predicts differences in breast density, bone density, steroid hormones, SHBG, and 2-OHE 1:16ct-OHE 1 independently of other factors associated with these measures. If equol-producer phenotype can predict differences in cumulative estrogen exposure / metabolism, it may serve as an early marker of breast cancer risk.
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