[en] INTRODUCTION: Overexpression of the ERBB2 oncogene is observed in about 20% of human breast tumors and is the consequence of increased transcription rates frequently associated with gene amplification. Several studies have shown a link between activator protein 2 (AP-2) transcription factors and ERBB2 gene expression in breast cancer cell lines. Moreover, the Yin Yang 1 (YY1) transcription factor has been shown to stimulate AP-2 transcriptional activity on the ERBB2 promoter in vitro. In this report, we examined the relationships between ERBB2, AP-2alpha, and YY1 both in breast cancer tissue specimens and in a mammary cancer cell line. METHODS: ERBB2, AP-2alpha, and YY1 protein levels were analyzed by immunohistochemistry in a panel of 55 primary breast tumors. ERBB2 gene amplification status was determined by fluorescent in situ hybridization. Correlations were evaluated by a chi2 test at a p value of less than 0.05. The functional role of AP-2alpha and YY1 on ERBB2 gene expression was analyzed by small interfering RNA (siRNA) transfection in the BT-474 mammary cancer cell line followed by real-time reverse transcription-polymerase chain reaction and Western blotting. RESULTS: We observed a statistically significant correlation between ERBB2 and AP-2alpha levels in the tumors (p < 0.01). Moreover, associations were found between ERBB2 protein level and the combined high expression of AP-2alpha and YY1 (p < 0.02) as well as between the expression of AP-2alpha and YY1 (p < 0.001). Furthermore, the levels of both AP-2alpha and YY1 proteins were inversely correlated to ERBB2 gene amplification status in the tumors (p < 0.01). Transfection of siRNAs targeting AP-2alpha and AP-2gamma mRNAs in the BT-474 breast cancer cell line repressed the expression of the endogenous ERBB2 gene at both the mRNA and protein levels. Moreover, the additional transfection of an siRNA directed against the YY1 transcript further reduced the ERBB2 protein level, suggesting that AP-2 and YY1 transcription factors cooperate to stimulate the transcription of the ERBB2 gene. CONCLUSION: This study highlights the role of both AP-2alpha and YY1 transcription factors in ERBB2 oncogene overexpression in breast tumors. Our results also suggest that high ERBB2 expression may result either from gene amplification or from increased transcription factor levels.
Allouche, Abdelkader; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire de Pathologie Expérimentale
Nolens, Gregory ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire d'Oncologie Moléculaire
Tancredi, Annalisa ; Université de Liège - ULiège > Département des sciences de la santé publique > Ecole de santé publique
Delacroix, Laurence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire d'Oncologie Moléculaire
Mardaga, Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire de Pathologie Expérimentale
Fridman, Viviana ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Winkler, Rose ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire d'Oncologie Moléculaire
Boniver, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire de Pathologie Expérimentale
Begon, Dominique ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Laboratoire de Pathologie Expérimentale
Language :
English
Title :
The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors.
Alternative titles :
[fr] L'immunodétection combinée des facteurs de transcription AP-2alpha et YY1 est associée à la surexpression du gène ERBB2 dans les tumeurs primaires du sein.
Télévie Fonds Léon Fredericq CAC - Centre anticancéreux près l'Université de Liège asbl Fondation contre le Cancer
Funding text :
The authors thank Estelle Dortu and the Centre for Research on Prion
Proteins from the University of Liege for technical assistance. This work
was supported by grants from Televie (Belgium), the Leon Fredericq
Foundation (Liege, Belgium), the Anticancer Centre attached to the University of Liege, and the Belgian Federation Against Cancer. AA
received a mixed doctorate grant from the Belgian Directorate-General
for Development Cooperation. GN, JM, and DYB are recipients of a Televie
Grant from the Belgian National Fund for Scientific Research
(F.N.R.S.). RW and PD are Research Directors from the F.N.R.S.
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