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

Abstract

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-, and 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 for 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. In prestasis human mammary epithelial cells, 24-hour treatment with EGFR (lapatinib) or KIT (ripretinib) inhibitors increased cyclin-dependent kinase inhibitors, decreased cyclins/cyclin-dependent kinase 4/6, and enforced G₁ arrest; EGFR inhibition also increased apoptosis. Together, these data identify a coordinated EGFR/KIT-linked proliferative bias in NHBW epithelium that is rapidly reversible in vitro, supporting validation in larger cohorts and pharmacodynamic window studies.