title: Toward the prognostic significance and therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer.
abstract: OBJECTIVE
  Abnormal accumulation and dysregulation of the epidermal growth factor receptor family member HER3 is associated with the development of various human cancers including those of the breast, lung, and ovary. We have previously shown that in melanoma HER3 is frequently overexpressed and is associated with poor prognosis. However, the importance of HER3 in colon cancer and its putative prognostic significance is still unknown.
  
  
  METHODS
  HER3 expression was analyzed in primary colon tumors from 110 patients by immunohistochemistry and correlated with time of progression. Parallel to this, the influence of HER3 overexpression on cell proliferation, migration, invasion, and apoptosis was investigated in four different colon cancer cell lines including DLD-1, LoVo, CaCO2, and T-84.
  
  
  RESULTS
  HER3 was detected at high frequency and exclusively at the membrane of the primary tumors. Elevated HER3 expression levels may serve as a putative prognostic marker because it associates with cell proliferation and decreased time to disease progression. High HER3 protein expression as well as phosphorylation levels were detected in tested cells. HER3 downregulation by RNA interference abrogated cell proliferation, migration, and invasion. In addition, suppression of HER3 resulted in a G(2)-M cell-cycle arrest, induced apoptosis, and led to morphologic changes in colon cancer cell lines. Furthermore, application of a monoclonal antibody specific to the extracellular portion of the receptor reduced heregulin-β1-induced migration and invasion and also induced apoptosis in colon cancer cell lines.
  
  
  CONCLUSIONS
  We postulate that HER3 is critically involved in colon cancer progression and may serve as a novel target for therapeutic intervention.
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Munich, Germany.
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Beji
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.forename: Jutta
authors.initials: J
authors.lastname: Engel
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000401:mortality; D015870:Gene Expression; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; C087230:heregulin beta1; D020893:Receptor, ErbB-3