A Hybrid Lock Score Defines a Transitional ER+ Tumor State and Links Regulatory Plasticity to Early Mortality

Poster presented at the ISCB Intelligent Systems for Molecular Biology (ISMB) 2026 conference. Estrogen receptor–positive (ER+) breast cancer is traditionally modeled as a stable luminal disease state; however, increasing evidence suggests that some tumors occupy intermediate phenotypes marked by partial epithelial loss and enhanced transcriptional plasticity. Here, we identify a previously under-characterized Transitional ER+ state and introduce the Hybrid Lock (HL) score, a quantitative metric capturing regulatory balance between luminal identity (ESR1 signaling) and epithelial-to-mesenchymal transition (EMT) programs using bulk transcriptomic data.Applied to The Cancer Genome Atlas ER+ tumors (n=568), HL revealed a continuous spectrum of regulatory states rather than discrete categories. A transitional regime comprising ~15–20% of ER+ tumors showed concurrent ESR1 attenuation and EMT activation. HL was inversely correlated with ESR1 expression (r≈−0.70) and positively correlated with canonical EMT signatures (r≈0.80). Transitional tumors also demonstrated elevated EZH2 expression (p<0.001), implicating epigenetic repression as a potential driver of plasticity.We validated HL in the independent METABRIC ER+ cohort (n≈1,300). Lower HL stratified patients with significantly poorer overall survival. In time-stratified Cox modeling, lower HL was strongly associated with increased mortality risk during the first 5 years after diagnosis (HR≈1.57 per SD decrease, p<10⁻⁵), whereas associations beyond 5 years were attenuated (HR≈1.03). Kaplan–Meier analysis confirmed inferior survival in low-HL tumors (log-rank p<0.01).These findings define a measurable intermediate ER+ state and establish HL as a reproducible framework linking transcriptional plasticity, epigenetic dysregulation, and early adverse outcomes in breast cancer.