Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients

• DOI: 10.1677/erc-08-0009
• Publication Date: 2008-05-10T01:06:57Z
• Authors: M. F Dillon; A. T Stafford; G. Kelly; A. M Redmond; M. McIlroy; T. B Crotty; E McDermott; A. D Hill; L. S Young
• Keywords: Cell Nucleus; Mitogen-Activated Protein Kinase 3; Antineoplastic Agents, Hormonal; Receptor, ErbB-2; Carcinoma; Breast Neoplasms; Prognosis; Survival Analysis; 3. Good health; Cohort Studies; Tamoxifen; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Cyclooxygenase 2; Disease Progression; Humans; Female; Tissue Distribution; Transcription Factors

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.