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

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 the 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. the 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

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast:a cross-sectional study of women with benign breast disease

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area (“TDLU count”), median TDLU diameter (“TDLU span”), and number of acini per TDLU (“acini count”). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-016-0678-4) contains supplementary material, which is available to authorized users