Abstract 7476: Characterizing the molecular drivers of terminal duct lobular unit involution and associations with breast cancer in African American women

Abstract Background: Terminal duct lobular units (TDLUs) are the functional units of the mammary gland, consisting of a terminal duct and the surrounding lobular tissue. These structures are key in the process of milk production and secretion, particularly in women of reproductive age. TDLUs are important in the context of breast pathology, as they can be sites of various benign and malignant changes, such as fibroadenomas or breast cancer. TDLU involution refers to the process of regression (or shrinking) of TDLUs as women age, particularly after menopause. Incomplete or delayed involution may be associated with an increased risk of breast cancer, as persistent epithelial tissue may remain susceptible to malignant changes. Differences in TDLU involution have been observed in the context of self-reported race, generating a gap in knowledge regarding the differential molecular regulation of TDLU involution by race and genetic ancestry. Our work aims to identify driver genes and pathways that regulate this process, as well as understand how these pathways are epigenetically modified, and possibly differ by race. Methods: Normal breast tissue from voluntary research biopsies were obtained from 94 pre-menopausal women (47 African American, 47 European American) between 2009-2019 from the Komen Tissue Bank. We performed both bulk RNAseq analyses and the EPIC850K methylation array to determine differences in cancer- and immune-related pathways associated with high and low TDLU counts (counts per mm2) stratified by self-reported race. Results: In African American women, 56 genes showed significant changes in gene expression associated with differential expression by TDLU counts per mm2, indicating differences in TDLU involution. Of these genes, LMOD1 and MFGE8 were associated with TDLU count (high/low) and were more significantly differentially expressed among African American women than European American women. LMOD1 is an actin-regulating protein that regulates cell shape, motility, and cytoskeleton remodeling. MFGE8 is a milk-fat globule epithelial growth factor that also mediates phagocytosis of apoptotic cells. Ingenuity Pathway Analysis revealed LMOD1 and MFGE8 interact via androgen receptor signaling in breast cancer. Further studies will investigate epigenetic modifications in these genes and those related directly to TDLU involution. Conclusions: Studying TDLU involution is crucial for understanding both the normal aging process of the breast and its implications for breast cancer risk. Understanding the molecular mechanisms behind TDLU involution, such as immune regulation and genetic factors, can help identify individuals at higher risk for breast cancer and inform preventive strategies. Citation Format: Jeri Danielle Hughes, Angel Hokulani Pajimola, Brittny Davis-Lynn, Sharon Fan, Mustapha Abubakar, Renata Cora, Alexandra Harris, Gretchen Gierach, Brittany Jenkins. Characterizing the molecular drivers of terminal duct lobular unit involution and associations with breast cancer in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7476.