Investigating AP-2 and YY1 protein expression as a cause of high HER2 gene transcription in breast cancers with discordant HER2 gene amplification.
BACKGROUND
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-2alpha and YY1 may cause Her2 protein overexpression independently of gene amplification.


METHODS
We characterised AP-2alpha/beta, AP-2alpha 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-2alpha/beta, AP-2alpha and YY1 was detected in 23%, 44% and 33% of cases respectively. AP-2alpha/beta 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-2alpha/beta 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-2alpha also correlated with luminal-type tumours but not with YY1 expression or good prognosis. AP-2alpha 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-2alpha but absence of AP-2alpha/beta and YY1 expression.


CONCLUSIONS
AP-2alpha/beta 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.
Powe
Desmond G
DG
Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham NG7 2UH, UK. des.powe@nottingham.ac.uk
Akhtar
Gulfareen
G
Habashy
Hany Onsy
HO
Abdel-Fatah
Tarek
T
Rakha
Emad A
EA
Green
Andrew R
AR
Ellis
Ian O
IO
D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D050656:Transcription Factor AP-2 / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D050986:YY1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics
D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D050656:Transcription Factor AP-2; D050986:YY1 Transcription Factor; C494698:YY1 protein, human