Relation of Serum Estrogen Metabolites with Terminal Duct Lobular Unit Involution Among Women Undergoing Diagnostic Image-Guided Breast Biopsy

Abstract

Higher levels of circulating estrogens and estrogen metabolites (EMs) have been associated with higher breast cancer risk. In breast tissues, reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have also been linked to elevated breast cancer risk. However, it is unknown whether reduced TDLU involution mediates the risk associated with circulating EMs. In a cross-sectional analysis of 94 premenopausal and 92 postmenopausal women referred for clinical breast biopsy at an academic facility in Vermont, we examined the associations of 15 EMs, quantified using liquid chromatography-tandem mass spectrometry, with number of TDLUs and acini count/TDLU using zero-inflated Poisson regression with a robust variance estimator and ordinal logistic regression models, respectively. All analyses were stratified by menopausal status and adjusted for potential confounders. Among premenopausal women, comparing the highest vs. lowest tertiles, levels of unconjugated estradiol (risk ratio [RR]=1.74, 95% confidence interval [CI]=1.06–2.87, p-trend=0.03), 2-hydroxyestrone (RR=1.74, 95% CI=1.01–3.01, p-trend=0.04), and 4-hydroxyestrone (RR=1.74, 95% CI=0.99–3.06, p-trend=0.04) were associated with significantly higher TDLU count. Among postmenopausal women, higher levels of estradiol (RR=2.09, 95% CI=1.01–4.30; p-trend=0.04) and 16α-hydroxyestrone (RR=2.27, 95% CI=1.29–3.99, p-trend=0.02) were significantly associated with higher TDLU count. Among postmenopausal women, higher levels of EMs, specifically conjugated estrone and 2- and 4-pathway catechols, were also associated with higher acini count/TDLU. Our data suggest that higher levels of serum EMs are generally associated with lower levels of TDLU involution.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast

“…We have recently developed quantitative measures of TDLU involution, including TDLU count standardized to tissue area and median acini count per TDLU, and found multiple associations with breast cancer risk factors including parity, menopausal status and circulating hormones among women who donated normal breast tissues. In women with benign breast disease, we have also found these TDLU measures to be related to breast cancer risk factors, including circulating insulin‐like growth factors, estrogens and mammographic density (MD) . This supports the notion that some breast cancer risk factors may influence their risk in part through delaying or inhibiting TDLU involution.…”

Serum insulin‐like growth factor (IGF)‐I and IGF binding protein‐3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank

“…19 The current analyses of women without BBD found an inverse association between circulating IGFBP-3 and TDLU count which was restricted to postmenopausal women but consistently found in both Caucasian and AA women; this inverse association agrees with the previous findings from postmenopausal Caucasian women with BBD. 19 The variation in associations by menopausal status may be due to the interaction of the IGF system with other endogenous hormones (e.g., estrogens 32, 48 ) that are present at higher levels in premenopausal women as well as the differences in levels of both IGF measures and TDLU involution by age. In the current analysis, the inverse association between postmenopausal IGFBP-3 levels and TDLU count was attenuated after additional adjustment for percentage of fat on the H & E slide in Caucasian, but not in AA, women.…”

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

“…Using normal breast tissues donated by volunteer participants in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center (KTB), we developed standardized, reproducible metrics for evaluating TDLU involution using digital images and demonstrated associations of these measures with multiple breast cancer risk factors [11, 16–20]. Acini counts are difficult to quantitate visually and image analysis tools have not yet been validated; therefore, to approximate the size and acini content within TDLUs, we recently developed TDLU span measures which are highly correlated with acini counts [4].…”