ESX - A STRUCTURALLY UNIQUE ETS OVEREXPRESSED EARLY DURING HUMAN BREAST TUMORIGENESIS

The >30 known members of the Ets multigene family of transcriptional r egulators are increasingly being recognized for their involvement in e arly embryonic development and late tissue maturation, directing stage -specific and tissue-restricted programs of target gene expression. Id entifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, su ggesting that their oncogenic potential is determined by the program o f target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain h omologous to the Drosophila E74/human Elf-1 subfamily, an amino-termin al region (A-region or Pointed domain) homologous to the distantly rel ated Ets-l subfamily, and a serine-rich box homologous to the transact ivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-rest ricted with serine box) exhibits Ets-like DNA binding specificity in e lectrophoretic mobility shift assays and, in transient transfection as says, transactivates Ets-responsive promoter elements including that f ound in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregu lin-inducible and overexpressed in HER2/neu activated breast cancer ce lls. Tissue hybridization suggests that ESX becomes overexpressed at a n early stage of human breast cancer development known as ductal carci noma in situ (DCIS).