Investigating AP-2 and YY1 protein expression as a cause of high HER2 gene transcription in breast cancers with discordant HER2 gene amplification

Introduction: Candidacy for anti-HER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP-2α and YY1 may cause Her2 protein overexpression independently of gene amplification.Methods: We characterised AP-2α/β, AP-2α and YY1 with HER2 gene and protein expression, other relevant biomarkers, and clinical outcome using tissue microarrays (TMAs) and immunohistochemistry in a large (n = 1,176) clinically annotated series of early stage operable breast cancer. The associations and prognostic independence of AP-2 and YY1 was assessed in all patients and an oestrogen receptor negative subgroup.Results: Nuclear expression of AP-2α/β, AP-2α and YY1 was detected in 23%, 44% and 33% of cases respectively. AP-2α/β significantly correlated with YY1 and both markers were increased in luminal oestrogen receptor (ER) positive tumours of small size and low grade but only AP-2α/β correlated with good prognosis breast cancer specific survival and disease free interval (BCSS and DFI). These characteristics were lost in oestrogen receptor negative patients. AP-2α also correlated with luminal-type tumours but not with YY1 expression or good prognosis. AP-2α and YY1 showed a significant correlation with Her2 protein expression and in addition, YY1 correlated with HER2 gene expression. Discordant HER2 gene and protein expression was identified in six cases (0.71% of the study group) with four of these showing AP-2α but absence of AP-2α/β and YY1 expression.Conclusions: AP-2α/β and YY1 are markers of good prognosis principally due to their association with oestrogen receptor but are not independent predictors. Discordant HER2 protein/gene expression is a rare event that is not always explained by the actions of AP-2 and YY1. © 2009 Powe et al.; licensee BioMed Central Ltd.