ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis

Abstract

The 430 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-speci®c and tissue-restricted programs of target gene expression. Identi®able primarily by their 85 amino acid ETS DNAbinding 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 identi®ed 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 speci®city 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 ampli®ed 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).

Dual function of the epithelial specific ets transcription factor, ELF3, in modulating differentiation

“…Furthermore, ELF3 is a potent transactivator of the TGF-b II receptor that is mediated through binding to a 5'-GGAAACAGGAA-3' motif in reverse orientation at +13 to +24 in the TGF-b II receptor gene (Choi et al, 1998). The HER2/neu oncogene contains a GGAA element in its proximal promoter which is bound with high a nity by ELF3 resulting again in transactivation in breast cancer cells (Chang et al, 1997). However, in our current study we found that ELF3 acts as a transcriptional repressor in the context of the K4 promoter, an e ect that appears to be independent of binding to a classical ets site.…”

“…Jen was the term designated to this novel member that resulted from screening a human foreskin keratinocyte cDNA library with a conserved 3' region of the ets domain (Andreoli et al, 1997). A search of expressed sequence tags with an 8 amino acid motif of the carboxyl terminal region of the ets domain led to the identi®cation of the same factor, termed ESX for epithelial restricted with serine box (Chang et al, 1997). The employment of a yeast two-hybrid system by screening a human placenta cDNA library again yielded the same ets factor, and was designated ERT for ets-related transcription factor (Choi et al, 1998).…”

“…Currently, ELF3 is the name applied to this gene (Tymms et al, 1997;Oettgen et al, 1999), based upon its belonging to the ELF (E74-like-factor) subfamily of the ets transcription factor family (Laudet et al, 1999). Its genomic organization has been elucidated and the gene localizes to human chromosome 1 q32.1 ± q32.2, a region that is altered in several tumors (Tymms et al, 1997;Oettgen et al, 1997bOettgen et al, , 1999 which may in part account for ELF3 overexpression in breast carcinogenesis (Chang et al, 1997).…”

A novel transcription factor, ELF5, belongs to the ELF subfamily of ETS genes and maps to human chromosome 11p13–15, a region subject to LOH and rearrangement in human carcinoma cell lines

“…However, ELF3 is an example of an epithelial-speci®c ETS gene Oettgen et al, 1997;Chang et al, 1997). ELF5, similarly to ELF3, is not expressed in hematopoietic compartments, such as the thymus and spleen, but is expressed in organs such as lung, kidney, stomach and prostate.…”

“…Transformed breast epithelial cells, for example, have been shown to express ETS family members GABPa, PEA3, ELF1, ETS1 and ELK1 (Scott et al, 1994b;DelannoyCourdent et al, 1996), but expression of these ETS family members is not restricted to epithelial cells. One ETS family member, ELF3/ESX/ESE-1/ERT, has recently emerged with epithelial and epithelial-cancer speci®c expression Chang et al, 1997;Choi et al, 1998;Oettgen et al, 1997). Given the extensive involvement of ETS factors in tumorigenesis, it becomes important to identify any additional ETS genes that may also play oncogenic roles, especially those that may be involved in epithelially derived cancers.…”