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

Abstract

BackgroundTerminal 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.MethodsSerum 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.ResultsHigher 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.ConclusionsThese 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 materialThe online version of this article (doi:10.1186/s13058-016-0678-4) contains supplementary material, which is available to authorized users.

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

“…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].…”

“…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]. Further, mammographic density, a strong breast cancer risk factor, is also associated with levels of TDLU involution [12, 25–27], and data suggest that IGF signaling may be interrelated with both of these characteristics [16], [28]. These data support further studies using standardized measures of TDLU involution and mammographic density, which might enhance risk assessment among women with BBD.…”

“…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].…”

“…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].…”

Involution of breast tissue and mammographic density

“…Unlike in the study by Gierach et al [12], the associations in the current analysis did not differ by menopausal status. In a study from Vermont that examined the relationship between circulating IGF-1 and involution or breast density, the positive correlation between TDLU counts and percent density was not significant after adjustment for confounders [19]. …”