title: Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients.
abstract: Cyclooxygenase-2 (COX-2) is associated with breast tumour progression. Clinical and molecular studies implicate human epidermal growth factor receptor 2 (HER2) in the regulation of COX-2 expression. Recent reports raise the possibility that HER2 could mediate these effects through direct transcriptional mechanisms. The relationship between HER2 and COX-2 was investigated in a cohort of breast cancer patients with or without endocrine treatment. A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for HER2, ERK1/2, polyoma enhancer activator 3 (PEA3) and COX-2 expression. Subcellular localisation of HER2 was assessed by immunofluorescence and confocal microscopy. Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen. COX-2 expression associated with both membranous and nuclear expression of HER2 (P=0.0033 and P<0.00001 respectively). No association was detected between COX-2 and either ERK1/2 or PEA3 (P=0.7 and P=0.3 respectively). None of the markers were found to be independently prognostic. Membrane HER2, nuclear HER2 and COX-2, however, were all found to predict poor disease-free survival in patients on endocrine treatment (P=0.0017, P=0.0003 and P=0.0202 respectively). Moreover, patients who were positive for COX-2 predicted adverse effects of tamoxifen (P=0.0427). These clinical ex vivo data are consistent with molecular observations that HER2 can regulate COX-2 expression through direct transcriptional mechanisms. COX-2 expression correlates with disease progression on endocrine treatment. This study supports a role for COX-2 as a predictor of adverse effects of tamoxifen in breast cancer patients.
authors.affiliation: Department of Surgery, Royal College of Surgeons in Ireland, St Stephens Green, Dublin 2, Ireland.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Dillon
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Stafford
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Kelly
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Redmond
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Crotty
authors.forename: E
authors.initials: E
authors.lastname: McDermott
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Hill
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D016019:Survival Analysis; D013629:Tamoxifen / Q000009:adverse effects* / Q000627:therapeutic use; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051546:Cyclooxygenase 2; D048052:Mitogen-Activated Protein Kinase 3; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D014157:Transcription Factors; C065788:transcription factor PEA3; C496540:PTGS2 protein, human