Abstract：
:To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Peluffo G,Subedee A,Harper NW,Kingston N,Jovanović B,Flores F,Stevens LE,Beca F,Trinh A,Chilamakuri CSR,Papachristou EK,Murphy K,Su Y,Marusyk A,D'Santos CS,Rueda OM,Beck AH,Caldas C,Carroll JS,Polyak Kdoi
10.1158/0008-5472.CAN-18-3264subject
Has Abstractpub_date
2019-08-15 00:00:00pages
4173-4183issue
16eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-18-3264journal_volume
79pub_type
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