title: Outcome and human epidermal growth factor receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling.
abstract: BACKGROUND
  We have shown previously that whereas overexpression of human epidermal growth factor receptor (HER)1, HER2 and HER3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study, bromodeoxyuridine (BrdU)-derived proliferation indices are correlated with clinical outcome and HER1-4 status for further clarification of the differing roles for the HER family at a biological level.
  
  
  METHODS
  Seventy-eight invasive breast cancers had BrdU labelling in vivo to determine the BrdU labelling index (BLI) and the potential tumour doubling time (Tpot). Long-term clinical follow-up was available for these patients. We used immunohistochemistry to establish the HER1-4 status in 55 patients from the BrdU cohort.
  
  
  RESULTS
  We demonstrate a significant correlation between high BLI values and breast cancer-specific death (P = 0.0174). Low Tpot times were also significantly correlated with breast cancer-specific death (P = 0.0258). However, BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER1, HER2 or HER3 had significantly (P = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (P = 0.024). Conversely, HER4 positivity was significantly correlated (P = 0.013) with low BLI values, in line with previous data associating this receptor with good prognosis tumours.
  
  
  CONCLUSIONS
  These results support the hypothesis that HER1-3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role.
authors.affiliation: Endocrine Cancer Group, Division of Cancer Sciences and Molecular Biology, University Department of Surgery, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
authors.forename: Sian M
authors.initials: SM
authors.lastname: Tovey
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Witton
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stanton
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Reeves
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cooke
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D002455:Cell Division; D015331:Cohort Studies; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000032:analysis / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015993:Life Tables; D008207:Lymphatic Metastasis; D008408:Mastectomy; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D020893:Receptor, ErbB-3 / Q000032:analysis; D066247:Receptor, ErbB-4; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D013629:Tamoxifen; C587689:ERBB4 protein, human