Epidermal Growth Factor Receptor/KIT-Linked Proliferative Bias in Normal Breast Lobules from Matched Non-Hispanic Black and White Women Is Rapidly Reversible by Receptor Tyrosine Kinase Inhibition

Basal-like/triple-negative breast cancers occur disproportionately at younger ages among non-Hispanic Black women (NHBW), but whether normal breast epithelium shows measurable, reversible differences in proliferative signaling is unclear. Histologically normal lobules from parity/age/body mass index–matched NHBW and non-Hispanic White women (NHWW) donors (10 versus 10) were profiled using targeted transcriptomics (IO360/BC360) and whole-slide quantitative immunohistochemistry [epidermal growth factor receptor (EGFR), KIT, and cytokeratin-5]. Eighty-nine transcripts differed between groups at false discovery rate < 0.10, with EGFR and KIT elevated in NHBW lobules and enrichment of basal/receptor tyrosine kinase–linked programs. Quantitative immunohistochemistry confirmed higher protein in NHBW tissue; in lobule-level models, the group effect (NHBW – NHWW) was EGFR β = 0.055, P = 0.010; KIT β = 0.093, P = 0.0027; and cytokeratin-5 β = 0.126, P = 0.027. Lobule-level effects were estimated by ordinary least squares with cluster-robust SEMs; models were stratified by specimen type. Functional plausibility was assessed in prestasis human mammary epithelial cells exposed for 24 hours to clinically relevant EGFR (lapatinib) or KIT (ripretinib) inhibitors. In human mammary epithelial cells, short-term EGFR or KIT blockade increased cyclin-dependent kinase inhibitors and decreased cyclins/cyclin-dependent kinase 4/6, enforcing G 1 arrest; EGFR inhibition additionally increased apoptosis. Together, matched normal tissue and primary-cell data indicate a coordinated EGFR/KIT-linked proliferative bias in NHBW epithelium that is rapidly reversible in vitro . These findings motivate composition-aware validation in larger normal-tissue cohorts and pharmacodynamic window studies to test whether short-term receptor tyrosine kinase modulation can reset proliferation-biased states in at-risk breast epithelium.