title: CYT-1 isoform of ErbB4 is an independent prognostic factor in serous ovarian cancer and selectively promotes ovarian cancer cell growth in vitro.
abstract: OBJECTIVE
  ErbB4 is a member of the ErbB subfamily of receptor tyrosine kinases with a poorly understood biological role in ovarian cancer. Here, we have addressed the expression, subcellular localization, and prognostic relevance of ErbB4 and its alternatively spliced isoforms in serous ovarian adenocarcinoma.
  
  
  METHODS
  A tissue microarray including 482 samples was analyzed by immunohistochemistry, and a series of 198 samples by isoform-specific real-time RT-PCR. The data were statistically analyzed for associations with clinicopathological markers and survival. The functional effect of expressing the relevant ErbB4 isoforms in ovarian cancer cells was addressed by measuring colony formation in soft agar.
  
  
  RESULTS
  While ErbB4 immunoreactivity was present in 90% of the samples, total ErbB4 protein expression was not significantly associated with prognostic markers. However, real-time RT-PCR analysis of serous ovarian cancer samples indicated the presence of two alternatively spliced cytoplasmic isoforms of ERBB4, CYT-1 and CYT-2, previously demonstrated to mediate significantly different cellular activities. Expression of CYT-1, but not of CYT-2, was significantly associated with tumor grade (P=0.014) and poor overall survival (P=0.0028). CYT-1 expression was also an independent prognostic factor (P=0.021) in multivariate analysis of survival. Consistent with a biological effect specific for the one isoform, overexpression of ErbB4 CYT-1, but not of ErbB4 CYT-2, increased anchorage-independent growth of ovarian adenocarcinoma cells in vitro.
  
  
  CONCLUSIONS
  These results suggest that expression of a specific ErbB4 isoform, CYT-1, is associated with poor survival and enhanced growth in serous ovarian cancer.
authors: Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, Turku, Finland.
authors: Ilkka
authors: I
authors: Paatero
authors: Heini
authors: H
authors: Lassus
authors: Teemu T
authors: TT
authors: Junttila
authors: Matti
authors: M
authors: Kaskinen
authors: Ralf
authors: R
authors: Bützow
authors: Klaus
authors: K
authors: Elenius
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis* / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D066247:Receptor, ErbB-4; D046888:Tissue Array Analysis
chemical_list: D007527:Isoenzymes; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4