Age-related terminal duct lobular unit involution in benign tissues from Chinese breast cancer patients with luminal and triple-negative tumors

Changyuan Guo, Hyuna Sung, Shan Zheng, Jennifer Guida, Erni Li, Jing Li, Nan Hu, Joseph Deng, Jonine D. Figueroa, Mark E. Sherman, Gretchen L. Gierach, Ning Lu, Xiaohong R. Yang

Terminal duct lobular unit (TDLU) involution is a physiological process of breast tissue aging characterized by a reduction in the epithelial component. In studies of women with benign breast disease, researchers have found that age-matched women with lower levels of TDLU involution are at increased risk of developing breast cancer. We previously showed that breast cancer cases with core basal phenotype (CBP; estrogen receptor negative [ER(-)], progesterone receptor-negative [PR(-)], human epidermal growth factor receptor 2-negative [HER2(-)], cytokeratins (CK 5 or CK5/6)-positive [CK5/6(+)] and/or epidermal growth factor receptor-positive [EGFR(+)]) tumors had significantly reduced TDLU involution compared with cases with luminal A (ER(+) and/or PR(+), HER2(-), CK5/6(-), EGFR(-)) tumors from a population-based case-control study in Poland. We evaluated the association of TDLU involution with tumor subtypes in an independent population of women in China, where the breast cancer incidence rate, prevalence of known risk factors, and mammographic breast density are thought to be markedly different from those of Polish women. We performed morphometric assessment of TDLUs by using three reproducible semiquantitative measures that inversely correlate with TDLU involution (TDLU count/100 mm(2), TDLU span in micrometer, and acini count/TDLU) by examining benign tissue blocks from 254 age-matched luminal A and 250 triple-negative (TN; ER(-), PR(-), HER2(-), including 125 CBP) breast cancer cases treated in a tertiary hospital in Beijing, China. Overall, we found that TN and particularly CBP cases tended to have greater TDLU measures (less involution) than luminal A cases in logistic regression models accounting for age, body mass index, parity, and tumor grade. The strongest association was observed for tertiles of acini count among younger women (aged <50 years) (CBP vs. luminal A; ORtrend 2.11, 95% CI 1.22-3.67, P = 0.008). These data extend previous findings that TN/CBP breast cancers are associated with reduced TDLU involution in surrounding breast parenchyma compared with luminal A cases among Chinese women, providing further support for differences in the pathogenesis of these tumor subtypes.