PITX1 safeguards epithelial identity and restrains EMT plasticity

Abstract Epithelial cell identity is maintained by coordinated transcriptional and epigenetic programs that preserve tissue integrity and restrain epithelial–mesenchymal transition (EMT)–driven plasticity. Through integrative transcriptomic and chromatin accessibility analyses of human mammary epithelial cells, we identify the homeobox transcription factor PITX1 as a master regulator of epithelial fate and a potent suppressor of EMT. Loss of PITX1 alone is sufficient to induce transcriptional reprogramming, cytoskeletal remodeling, and morphological shifts characteristic of EMT, comparable to those elicited by TGF-β stimulation. Conversely, restoration of PITX1 in aggressive breast cancer cells markedly reduces their migratory capacity. In patient tumors, PITX1 is enriched in epithelial compartments and EMT‑low subtypes, but downregulated in mesenchymal‑like cancers. Clinically, high PITX1 expression correlates with lower tumor grade, improved survival, and enhanced chemotherapy sensitivity, whereas its loss marks aggressive, therapy‑resistant disease. Mechanistically, PITX1 directly binds and represses genes encoding core EMT drivers, thereby maintaining epithelial gene expression programs and establishing an epigenetic barrier to mesenchymal transition.