title: Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients.
abstract: BACKGROUND
  The HER (human EGFR related) family of receptor tyrosine kinases (HER1/EGFR (epidermal growth factor receptor)/c-erbB1, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4) shares a high degree of structural and functional homology. It constitutes a complex network, coupling various extracellular ligands to intracellular signal transduction pathways resulting in receptor interaction and cross-activation. The most famous family member is HER2, which is a target in Herceptin therapy in metastatic status and also in adjuvant therapy of breast cancer in the event of dysregulation as a result of gene amplification and resulting protein overexpression. The HER2-related HER receptors have been shown to interact directly with HER2 receptors and thereby mutually affect their activity and subsequent malignant growth potential. However, the clinical outcome with regard to total HER receptor state remains largely unknown.
  
  
  METHODS
  We investigated HER1-HER4, at both the DNA and the protein level, using fluorescence in situ hybridisation (FISH) probes targeted to all four receptor loci and also immunohistochemistry in tissue microarrays derived from 278 breast cancer patients.
  
  
  RESULTS
  We retrospectively found HER3 gene amplification with a univariate negative impact on disease-free survival (hazard ratio 2.35, 95% confidence interval 1.08 to 5.11, p = 0.031), whereas HER4 amplification showed a positive trend in overall and disease-free survival. Protein expression revealed no additional information.
  
  
  CONCLUSIONS
  Overall, the simultaneous quantification of HER3 and HER4 receptor genes by means of FISH might enable the rendering of a more precise stratification of breast cancer patients by providing additional prognostic information. The continuation of explorative and prospective studies on all HER receptors will be required for an evaluation of their potential use for specific therapeutic targeting with respect to individualised therapy.
authors.affiliation: Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sassen
authors.forename: Justine
authors.initials: J
authors.lastname: Rochon
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism; D003582:Cytogenetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D020893:Receptor, ErbB-3 / Q000235:genetics*; D066247:Receptor, ErbB-4; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4