title: Directing HER4 mRNA expression towards the CYT2 isoform by antisense oligonucleotide decreases growth of breast cancer cells in vitro and in vivo.
abstract: BACKGROUND
  The tyrosine kinase receptor HER4 is a member of the epidermal growth factor receptor (EGFR) family. It plays diverse roles in cancer development and cancer progression and can both exert oncogenic and tumour-suppressive activities. Alternatively spliced isoforms of HER4 are critical to the different signalling possibilities of HER4.
  
  
  METHODS
  We use a splice-switching oligonucleotide (SSO) to direct the alternative splicing of HER4 from the CYT1 to the CYT2 isoform in HER4-expressing breast cancer cells.
  
  
  RESULTS
  Treatment with a target-specific SSO was accompanied by a decreased growth of the cells (P<0.0001). In addition, the SSO treatment induced a decreased activity of Akt. We confirmed the SSO-dependent switching of the HER4 isoform CYT1 to CYT2 expression in a xenografted mouse tumour model driven by subcutaneously injected MCF7 cells. We hence demonstrated the feasibility of SSO-directed splice-switching activity in vivo. Furthermore, the SSO treatment efficiently decreased the growth of the xenografted tumour (P=0.0014).
  
  
  CONCLUSIONS
  An SSO directing the splicing of HER4 towards the CYT2 isoform has an inhibitory effect of cancer cell growth in vitro and in vivo. These results may pave the way for the development of new anticancer drugs in HER4-deregulated cancers in humans.
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Norrebrogade 44, Building 9, 8000 Aarhus C, Denmark.
authors.forename: T O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: S
authors.initials: S
authors.lastname: Sorensen
authors.forename: F
authors.initials: F
authors.lastname: Dagnæs-Hansen
authors.forename: J
authors.initials: J
authors.lastname: Kjems
authors.forename: B S
authors.initials: BS
authors.lastname: Sorensen
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011897:Random Allocation; D066247:Receptor, ErbB-4; D023041:Xenograft Model Antitumor Assays
chemical_list: D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4