Population-associated molecular variation in histologically normal breast tissue is context-dependent and associated with distinct transcriptional states

Population-associated molecular variation in breast tissue may contribute to differences in tissue biology and disease susceptibility, yet the extent to which such variation is shaped by underlying tissue states remains unclear. We performed integrated transcriptomic and lipidomic profiling of histologically normal breast tissue samples from African American and Caucasian White individuals. Unsupervised transcriptomic analysis revealed two baseline transcriptional states, G1 and G2, that defined the primary axis of molecular variation and corresponded to epithelial-enriched and vascular-enriched tissue contexts. Global comparisons between African American and Caucasian White samples showed limited transcriptomic differences. However, when samples were stratified by baseline transcriptional state, 191 genes were differentially expressed within G1, with coordinated upregulation of extracellular matrix organization and proliferative/cytoskeletal programs in African American samples. No comparable population-associated differences were observed within G2. Lipidomic analyses showed partial but non-significant trends consistent with transcriptomic structure. These findings suggest that population-associated molecular differences in normal breast tissue are context-dependent and emerge within specific baseline transcriptional states.