title: Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer.
abstract: OBJECTIVE
  DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.
  
  
  RESULTS
  DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.
  
  
  CONCLUSIONS
  In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.
authors.affiliation: Department of Pathology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Guus M
authors.initials: GM
authors.lastname: Bol
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: Vermeulen
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology*; D018797:Cell Cycle Proteins; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D053487:DEAD-box RNA Helicases; D066246:ErbB Receptors; D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D051881:Receptor, Notch1; D014157:Transcription Factors; C480519:COMMD1 protein, human; C108803:FOXO4 protein, human; C508053:ERBB2 protein, human; C494918:AKT1 protein, human; C119332:DDX3X protein, human