Abstract C143: Molecular drivers of terminal duct lobular unit involution: Associations with gene expression, genetic ancestry, and breast cancer disparties
Authors: Hughes Jeri D. , Pajimola Angel , Davis-Lynn Brittney , Cora Renata , Harris Alexandra , Gierach Gretchen , Jenkins-Lord Brittney 
Published: September 2024

Abstract
Terminal duct lobular units (TDLU) are epithelial sub-structures located within breast tissue that function in lactation during child-bearing age. TDLU involution is a mechanism whereby shrinking of these units occurs once child-bearing age has been surpassed, inducing a decrease in acini sub-structures and TDLU counts in healthy breast tissues. Decreased TDLU involution has one of the largest associations with breast cancer risk, and is linked to factors such as breastfeeding, parity, hormone levels, mammographic density, age, BMI, menopausal status, and SNP risk scores. Decreased TDLU involution is seen more commonly in women of African ancestry and has been implicated to increase the risk of breast cancer development in this population. The molecular and environmental factors that influence TDLU involution have not been fully characterized. Environmentally, previous studies have shown that increased air pollution exposure with PM2.5 components is related to higher TDLU counts and lower involution. Molecularly, our previous work has shown that high TDLU counts are associated with a more pro-inflammatory immune environment and may indicate that lower TDLU involution is a result of inflammation in the breast due to persistence of at-risk epithelial tissue. TDLU involution is measured by TDLU counts, acini counts per TDLU, and TDLU diameter. Bulk RNAseq data from voluntary research biopsies of normal breast tissue donated by a cohort of 94 women (47 African American, 47 European American) was analyzed for gene expression associations with TDLU counts and self-reported race. Analysis revealed thirteen cancer- and/or immune-related genes with significant changes in expression associated with high TDLU counts indicating lower TDLU involution. For two out of three genes most relevant to mammary biology, the relationship between gene expression and increasing TDLU count was more significant among African American women than European American women. Additionally, CIBERSORTx RNAseq analysis estimated the abundance of immune cell sub- populations, and revealed significant differences between women with high and low TDLU counts. There are also differences observed in gene expression across race for women with high TDLU count that may indicate a link between lower TDLU involution and race. These initial findings provide greater insight into the molecular mechanisms that drive lower TDLU involution overall and for certain populations. Future analyses will further link these molecular factors to environmental exposures, such as air pollution, to provide context to risk factors associated with decreased TDLU involution and increased breast cancer risk.
Citation Format: Jeri D. Hughes, Angel Pajimola, Brittney Davis-Lynn, Renata Cora, Alexandra Harris, Gretchen Gierach, Brittney Jenkins-Lord. Molecular drivers of terminal duct lobular unit involution: Associations with gene expression, genetic ancestry, and breast cancer disparties [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C143.