EN1 is a transcriptional dependency in triple-negative breast cancer associated with brain metastasis

To define transcriptional dependencies of triple-negative titative proteomic analyses of EN1-bound chromatin com-breast cancer (TNBC), we identified transcription factors high-plexes revealed association with transcriptional repressors and ly and specifically expressed in primary TNBCs and tested their coactivators including TLE3, TRIM24, TRIM28, and TRIM33. requirement for cell growth in a panel of breast cancer cell High expression of EN1 correlated with short overall survival lines. We found that EN1 (engrailed 1) is overexpressed in and increased risk of developing brain metastases in patients TNBCs and its downregulation preferentially and significantly with TNBC. Thus, EN1 is a prognostic marker and a potential reduced viability and tumorigenicity in TNBC cell lines. By therapeutic target in TNBC. integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes Significance: These findings show that the EN1 transcrip-involved in WNT and Hedgehog signaling, neurogenesis, and tion factor regulates neurogenesis-related genes and is associ-axonal guidance as direct EN1 transcriptional targets. Quan-ated with brain metastasis in triple-negative breast cancer.