Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology

Abstract

Background: Greater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized.

Methods: To study this question, we developed three reproducible measures that are inversely associated with TDLU involution: TDLU counts, median TDLU span, and median acini counts/TDLU. We determined factors associated with TDLU involution using normal breast tissues from 1938 participants (1369 premenopausal and 569 postmenopausal) ages 18 to 75 years in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Multivariable zero-inflated Poisson models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) for factors associated with TDLU counts, and multivariable ordinal logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for factors associated with categories of median TDLU span and acini counts/TDLU.

Results: All TDLU measures started declining in the third age decade (all measures, two-sided P trend ≤ .001); and all metrics were statistically significantly lower among postmenopausal women. Nulliparous women demonstrated lower TDLU counts compared with uniparous women (among premenopausal women, RR = 0.79, 95% CI = 0.73 to 0.85; among postmenopausal, RR = 0.67, 95% CI = 0.56 to 0.79); however, rates of age-related TDLU decline were faster among parous women. Other factors were related to specific measures of TDLU involution.

Conclusion: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies.

Figure 1.

Terminal duct lobular unit (TDLU) involution assessment in the Susan G. Komen Tissue Bank. Three quantitative measures (TDLU count, TDLU span, and number of acini per TDLU) associated with reduced levels of TDLU involution were assessed from digitized images of H&E stained tissue sections. A) A digital H&E section with multiple TDLUs (TDLU count). For up to 10 TDLUs per section, the longest TDLU span was measured in microns and the counts of acini/TDLU in categories (1 = <10, 2 = 11–20, 3 = 21–30, 4 = 31–50, and 5 = 51+) recorded (0.75x). B) Representative TDLUs for which the longest TDLU span was measured in microns using a digital ruler (4.27x). A representative acinus is circled in red and indicated with an arrow.

Figure 2.

Relationship between age and terminal duct lobular unit (TDLU) counts, TDLU span, and category of acini counts/TDLU. A lowess function was used to estimate the average of TDLU counts, median TDLU span, and median acini counts/TDLU, as a function of age. The number of acini/TDLU was recorded in categories (1 = <=10, 2 =11–20, 3 =21–30, 4 = 31–50, and 5 = 51+). TDLU = terminal duct lobular unit.

Figure 3.

Impact of parity on the association between TDLU counts and age. A lowess function was used to estimate the average of TDLU counts stratified by parity status as a function of age. TDLU = terminal duct lobular unit.