Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a breast cancer master regulator that restricts cells to a luminal non-migratory phenotype

Despite considerable efforts to understand the biology of breast cancer, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlay oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer, but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to the luminal subtype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/b-catenin pathway, and the pro-metastatic TGFb. Our study reveals ThPOK as a breast cancer master transcription factor with opposing forces to the acquisition of metastatic features.