title: ELF5 isoform expression is tissue-specific and significantly altered in cancer.
abstract: BACKGROUND
  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 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.
  
  
  METHODS
  RNA-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.
  
  
  RESULTS
  ELF5 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.
  
  
  CONCLUSIONS
  Alternative 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.
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. c.piggin@garvan.org.au.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Piggin
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. d.roden@garvan.org.au.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Roden
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. d.gallego@garvan.org.au.
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. heather.lee@babraham.ac.uk.|Babraham Institute, Cambridge, CB22 3AT, UK. heather.lee@babraham.ac.uk.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. s.oakes@garvan.org.au.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
authors.affiliation: Cancer Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. c.ormandy@garvan.org.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C116038:ELF5 protein, human; D020033:Protein Isoforms; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors