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

Q: What evidence shows a proliferative signaling bias in normal breast lobules?

Targeted transcriptomics and whole-slide quantitative immunohistochemistry identified elevated EGFR and KIT in matched non-Hispanic Black lobules, along with enrichment of basal/RTK-linked programs and higher EGFR/KIT-related protein levels.

Q: Which inhibitors were used to test functional reversibility, and what was observed?

EGFR was inhibited with lapatinib and KIT with ripretinib for 24 hours in prestasis human mammary epithelial cells, which increased CDK inhibitors, decreased cyclins/CDK4/6, enforced G1 arrest, and increased apoptosis with EGFR inhibition.

Q: Why is the study important for understanding breast cancer disparities?

It tests whether early-life, tissue-intrinsic determinants can be detected in histologically normal breast tissue, providing mechanistic support for a receptor tyrosine kinase-linked proliferative bias that may contribute to disproportionate risk.

Sep 22, 2026

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Basal-like/triple-negative breast cancers arise disproportionately in non-Hispanic Black women, but whether normal breast epithelium shows measurable, reversible proliferative signaling differences is unclear. Histologically normal lobules from parity-, age-, and BMI-matched non-Hispanic Black and non-Hispanic White donors were profiled using targeted transcriptomics and whole-slide quantitative immunohistochemistry for EGFR, KIT, and cytokeratin-5. EGFR and KIT were elevated with enrichment of basal/RTK-linked programs, and quantitative assays confirmed higher protein in non-Hispanic Black tissue. In prestasis human mammary epithelial cells, EGFR (lapatinib) or KIT (ripretinib) inhibition increased CDK inhibitors, reduced cyclins/CDK4/6, enforced G1 arrest, and EGFR blockade also increased apoptosis. Results support a coordinated EGFR/KIT-linked proliferative bias that is rapidly reversible in vitro.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Background and rationale

Disparities and field cancerization

Candidate epithelial receptor tyrosine kinase programs

Study design and methods

Matched donor tissue profiling

Targeted transcriptomics and quantitative immunohistochemistry

Functional inhibition in human mammary epithelial cells

Results

Differential EGFR/KIT signaling in normal lobules

Quantitative protein validation

Effects of EGFR and KIT inhibitors on cell cycle and apoptosis

Conclusions and implications

Rapid reversibility and next-step validation

The American Journal of Pathology, Vol. 196, No. 5, May 2026 EPITHELIAL AND MESENCHYMAL CELL BIOLOGY 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 Joshua W. Ogony, *† Nicole Cruz-Reyes, * Laura Pacheco-Spann,† Amanda Arnold,‡ Sarah McLaughlin,§ Amy C. Degnim,¶ Stacey J. Winham, || Mark E. Sherman, *† and Derek C. Radisky * From the Departments of Cancer Biology,* Quantitative Health Sciences,† Research,‡ and Surgery,§ Mayo Clinic College of Medicine, Jacksonville, Florida; and the Departments of Surgery¶ and Quantitative Health Sciences,|| Mayo Clinic College of Medicine, Rochester, Minnesota Accepted for publication February 2, 2026. Address correspondence to Derek C. Radisky, Ph.D., Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224. E-mail: radisky.derek@mayo. edu. Basal-like/triple-negative breast cancers occur disproportionately at younger ages among nonHispanic 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 lobulelevel 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 cyclindependent 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. (Am J Pathol 2026, 196: 1133—1146; [https://doi.org/10.1016/j.ajpath.2026.02.003](https://doi.org/10.1016/j.ajpath.2026.02.003)) Triple-negative/basal-like breast cancers occur nearly twice as often in non-Hispanic Black women (NHBW) and account for excess breast cancer mortality even after adjustment for access-to-care variables.1—6 The disparity is most pronounced before the age of 40 years; established reproductive and lifestyle factors explain only part of the excess incidence, suggesting race-associated, tissue-intrinsic determinants that operate early in life.4,7 Signals consistent with such determinants can be detected in histologically normal breast tissue (often termed field cancerization) . Reduction-mammoplasty cohorts of African American donors have reported raceassociated shifts in proliferation programs, DNA-repair pathways, and DNA-methylation landscapes.8—10 However, these data sets are largely descriptive, frequently underpowered for parity-matched comparisons, and rarely paired with functional validation, leaving the mechanistic basis of any proliferative field unresolved. Among candidate epithelial programs with plausibility for early-life effects are receptor tyrosine kinase (RTK) pathways centered on epidermal growth factor receptor Supported by National Cancer Institute grants R01 CA229811, CA237602, and CA262393 (A.C.D., M.E.S., and D.C.R.), along with an administrative supplement to R01 CA237602 (J.O., M.E.S., and D.C.R.) . J.W.O. and N.C.-R. share first authorship. ª 2026 The Author(s) . Pub

FAQs

What evidence shows a proliferative signaling bias in normal breast lobules?

Targeted transcriptomics and whole-slide quantitative immunohistochemistry identified elevated EGFR and KIT in matched non-Hispanic Black lobules, along with enrichment of basal/RTK-linked programs and higher EGFR/KIT-related protein levels.

Which inhibitors were used to test functional reversibility, and what was observed?

EGFR was inhibited with lapatinib and KIT with ripretinib for 24 hours in prestasis human mammary epithelial cells, which increased CDK inhibitors, decreased cyclins/CDK4/6, enforced G1 arrest, and increased apoptosis with EGFR inhibition.

Why is the study important for understanding breast cancer disparities?

It tests whether early-life, tissue-intrinsic determinants can be detected in histologically normal breast tissue, providing mechanistic support for a receptor tyrosine kinase-linked proliferative bias that may contribute to disproportionate risk.

Sep 22, 2026

Upload by Asher