ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis.
The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable 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, suggesting that their oncogenic potential is determined by the program of 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 homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-1 subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found 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 heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).
Chang
C H
CH
Cancer Research Institute and Division of Oncology-Hematology, University of California at San Francisco, 94143, USA.
Scott
G K
GK
Kuo
W L
WL
Xiong
X
X
Suzdaltseva
Y
Y
Park
J W
JW
Sayre
P
P
Erny
K
K
Collins
C
C
Gray
J W
JW
Benz
C C
CC
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D017781:Genes, Immediate-Early; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C105529:ELF3 protein, human; C494041:ETS1 protein, human