ERBB Receptor Regulation of ESX/ELF3 Promotes Invasion in Breast Epithelial Cells

ERBB2 amplification and overexpression in human breast cancer is associated with poor outcome. However, over-expression of ERBB2 alone is an early event in breast tumorigenesis, suggesting secondary events are required for progression. Here we demonstrate that the Ets transcription factor, ESX, induces an invasive phenotype in breast epithelial cells mediated through transcriptional targets of ESX. In non-transformed cells this process is regulated by EGF signaling. Expression of ERBB2 facilitates EGF-independent regulation of ESX levels, thus promoting invasion. Our data define mechanisms by which ERBB2 overexpression promotes breast cancer invasiveness and progression, and provide a model to understand the clinical behavior of this subset of human tumors and identify potential therapeutic targets to improve patient outcome.