Stuck Between and Silenced: A Hidden Transitional State in ER+ Breast Cancer Disparities

Overview

Black women die from ER-positive breast cancer at higher rates than white women despite similar diagnoses. This study tested whether ER-positive (ER+) tumors lie on a continuous EMT–ESR1 landscape containing a hidden Transitional state with ancestry-associated regulatory differences that predict survival. Using TCGA-BRCA (n=568), a reference-anchored Hybrid Lock Score quantified epithelial–mesenchymal regulatory balance. In the high-risk Transitional (low ER+, higher EMT) subset (n=154), Black patients had higher scores (g=0.71, p=0.006), lower GREB1 (g=−0.741, p=0.0014), reduced inflammatory signaling (g=−0.441, p=0.042), and reduced occupancy of the Transitional state (30% vs 70%), consistent with EZH2-associated epigenetic silencing and immune suppression. EZH2 inhibition in MCF-7 cells shifted the score directionally. In independent METABRIC validation (n=383), higher scores predicted worse survival, with ~80% higher risk of death in the first 5 years (HR = 1.80, p ≈ 1×10⁻⁵), identifying a pre-treatment molecular axis differing by ancestry and independently predicting early mortality.