<i>EN1</i> Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis

Guillermo Peluffo(Harvard University), Ashim Subedee(Harvard University), Nicholas W. Harper(Dana-Farber Cancer Institute), Natalie L. Kingston(Dana-Farber Cancer Institute), Bojana Jovanović(Harvard University), Felipe N. Flores(Harvard University Press), Laura E. Stevens(Harvard University), Francisco Beça(Beth Israel Deaconess Medical Center), Anne Trinh(Harvard University), Chandra Sekhar Reddy Chilamakuri(Bridge University), Evangelia K. Papachristou(Bridge University), Katherine C. Murphy(Dana-Farber Cancer Institute), Ying Su(Harvard University), Andriy Marusyk(Harvard University), Clive S. D’Santos(Bridge University), Oscar M. Rueda(Bridge University), Andrew H. Beck(Beth Israel Deaconess Medical Center), Carlos Caldas(Bridge University), Jason S. Carroll(Bridge University), Kornélia Polyák(Harvard University)
Cancer Research
June 25, 2019
10.1158/0008-5472.can-18-3264
Cited by 68Open Access
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Abstract

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.

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