A FOXA1/SPDEF Co-regulatory Axis Maintains Luminal Identity in HER2-Positive Breast Cancer by Driving ERBB2 Expression and Suppressing a TEAD/YAP-Driven EMT Program [ATAC-seq]

Here, we solve this enigma by addressing this question through the identification of an indispensable, co-dependent regulatory circuit formed between FOXA1 and the SAM pointed domain containing ETS-family transcription factor (SPDEF).

Using integrative multi-omics analyses of patient tumors and experimental models, we demonstrate that this circuit functions as the master guardian of the HER2-positive luminal state. It executes this role via two distinct, essential mechanisms: it directly binds regulatory elements to drive high-level expression of the ERBB2 oncogene, and it simultaneously preserves epithelial identity by suppressing a latent program of epithelial-to-mesenchymal transition (EMT).