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

Desmond G Powe,Tarek Abdel-Fatah,Emad A Rakha,Gulfareen Akhtar,Andrew R Green,Hany Onsy Habashy,Ian O Ellis

doi:10.1186/bcr2461

Abstract

IntroductionCandidacy 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.MethodsWe 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.ResultsNuclear 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.ConclusionsAP-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.

Highlights

Introduction Candidacy for antiHER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP2α and Yin Yang protein-1 (YY1) may cause Her2 protein overexpression independently of gene amplification
Positive AP-2α/β expression was more frequent in lobular breast cancer (BC) compared to negative cases (17.1% compared to 8.3%, respectively) showing good NPI (P < 0.001) and reduced vascular invasion (P = 0.036)
AP-2α/β isoforms: AP-2α/β expression was significantly associated with longer breast cancer specific survival (BCSS) (Log rank (LR) = 7.607, P = 0.006; Hazard ratios (HR) = 1.5, P = 0.006; Figure 2) and an increased disease free interval (DFI) (LR = 9.201, P = 0.002; HR = 1.565, P = 0.003; Figure 3) but not for distant metastasis (DM) formation or tumour recurrence

Summary

Introduction

HER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP2α and YY1 may cause Her protein overexpression independently of gene amplification. Over-expression of HER2 is generally seen in high grade breast cancers and is associated with aggressive tumour growth characteristics including increased proliferation [3], enhanced tumorigenicity [4] and metastatic potential [5]. These adverse properties can be ameliorated by blockade of HER2 protein with the humanised monoclonal antibody, trastuzumab, and is targeted at patients that show HER2 amplification [6]. At least four binding sites have been identified for AP-2 in the promoter of the HER2 gene [13,14] and some studies have shown a correlation between the expression of AP-2 with HER2 overexpression in breast cancer cell lines [12,13,14,15] suggesting that AP-2 and its neutralisation could be a means of down regulating HER2 [15]

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