Abstract
BackgroundE74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. ELF5 also plays key roles in malignancy, particularly in basal-like and endocrine-resistant forms of breast cancer. Almost all genes undergo alternative transcription or splicing, which increases the diversity of protein structure and function. Although ELF5 has multiple isoforms, this has not been considered in previous studies of ELF5 function.MethodsRNA-sequencing data for 6757 samples from The Cancer Genome Atlas were analyzed to characterize ELF5 isoform expression in multiple normal tissues and cancers. Extensive in vitro analysis of ELF5 isoforms, including a 116-gene quantitative polymerase chain reaction panel, was performed in breast cancer cell lines.ResultsELF5 isoform expression was found to be tissue-specific due to alternative promoter use but altered in multiple cancer types. The normal breast expressed one main isoform, while in breast cancer there were subtype-specific alterations in expression. Expression of other ETS factors was also significantly altered in breast cancer, with the basal-like subtype demonstrating a distinct ETS expression profile. In vitro inducible expression of the full-length isoforms 1 and 2, as well as isoform 3 (lacking the Pointed domain) had similar phenotypic and transcriptional effects.ConclusionsAlternative promoter use, conferring differential regulatory responses, is the main mechanism governing ELF5 action rather than differential transcriptional activity of the isoforms. This understanding of expression and function at the isoform level is a vital first step in realizing the potential of transcription factors such as ELF5 as prognostic markers or therapeutic targets in cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0666-0) contains supplementary material, which is available to authorized users.
Highlights
E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland
ELF5 isoforms are differentially expressed in normal tissues There are four ELF5 transcript variants in the National Center for Biotechnology Information RefSeq database [58], predicted to produce four unique proteins (Fig. 1)
The two full-length transcripts use alternative promoters, resulting in unique first exons and proteins that differ by only ten N-terminal amino acids
Summary
E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. Transcription factors are the integrators of multiple signaling pathways, converting internal and external stimuli into changes in gene expression. Through this role, the evolutionarily conserved E26 transforming sequence (ETS) transcription factor family controls fundamental cellular processes such as proliferation, differentiation, and apoptosis [1]. In addition to the ETS domain, the full-length ELF5 protein contains an N-terminal Pointed (PNT) domain (83 amino acids) that is similar to the evolutionarily conserved sterile alpha motif (SAM) domain. SAM domains have diverse functions, including protein–protein interactions, Piggin et al Breast Cancer Research (2016) 18:4 polymerization, kinase docking, RNA binding, and lipid molecule interactions [8,9,10,11]. The ELF5 PNT domain has been shown to have strong transactivation activity [12]; the mechanisms underlying this activity (for example, protein–protein interactions or posttranslational modifications) are unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
