Circulating Sex Hormones and Terminal Duct Lobular Unit Involution of the Normal Breast

Abstract

Background Terminal duct lobular units (TDLUs) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). Methods We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n=390): TDLU counts, median TDLU span, and median acini counts per TDLU. Relative risks (RRs, for continuous measures), odds ratios (ORs, for categorical measures), 95% confidence intervals (CIs), and p-trends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. Results Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18, 95% CI: 1.07-1.31; p-trend=0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80, 95% CI: 0.72-0.89; p-trend<0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61, 95% CI: 1.32-1.97; p-trend<0.0001) and testosterone (RRT3vsT1: 1.32, 95% CI: 1.09-1.59; p-trend=0.0043) were associated with higher TDLU counts. Conclusions These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. Impact Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis.

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

“…This work extends prior research in this cohort linking decreased TDLU involution to increased risk of developing breast cancer [7, 15]. We note that several groups have developed automated methods to assess TDLU histology and to estimate levels of involution [15, 17, 18, 33, 34] that agree well with visual assessment. Hence, we view visual assessment of involution levels as a temporary approach to advance this area as automated algorithms are developed.…”

“…Prior analyses demonstrating associations between breast cancer risk factors and the TDLU involution metrics evaluated here support that these are biologically plausible markers of risk [11, 16, 17]. Levels of TDLU involution increase with age and menopause, paralleling the slower rise in breast cancer incidence rates around age 50 years, a surrogate for menopause [24].…”

“…However, TDLU involution has not informed questions about the protective effect of pregnancy and breast cancer diagnosed at older ages, supporting a role for other mechanisms, including molecular changes, which may be related to the protective effect of parity [29, 30]. Additionally, data suggest that involution is inversely related to circulating concentrations of factors associated with elevated breast cancer risk, such as prolactin, testosterone, and postmenopausal estrogens, as well as use of menopausal hormone therapy [11, 16, 17]. Exposures such as smoking, which may reduce estrogenic effects, have also shown an association with increased TDLU involution [4].…”

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

“…Up to 10 TDLUs were evaluated for maximum diameter as “TDLU span” (measured with an electronic ruler in microns) to provide reliable estimates (17). A semi-automated image analysis tool was used to estimate the number of acini per TDLU as previously described (18, 19). Median values for each woman were used as summary measures of TDLU span and acini count.…”

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

“…One previous study of TDLU involution among women without BBD measured serum estradiol using an immunoassay and reported that elevated estradiol levels were associated with higher TDLU count [21]. Herein, we used a high-performance liquid chromatography-tandem mass spectrometry (LC/MS-MS) assay to refine measurements and extended the analysis to examine detailed patterns of estrogen metabolism in relation to highly reliable measures of TDLUs and acini count/TDLU in the background normal breast tissue from women undergoing diagnostic breast biopsy.…”