AP-2γ promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene

• Published in: The EMBO journal Vol. 28; no. 22; pp. 3591 - 3601
• Main Authors: Williams, Christopher M J, Scibetta, Angelo G, Friedrich, J Karsten, Canosa, Monica, Berlato, Chiara, Moss, Charlotte H, Hurst, Helen C
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 18-11-2009; Nature Publishing Group UK; Nature Publishing Group
• Subjects: AP-2 factors; breast cancer; EMBO24; p21cip; transcriptional repression; AP‐2 factors; breast cancer; transcriptional repression; p21cip
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.290

Overexpression of the activator protein (AP)‐2γ transcription factor in breast tumours has been identified as an independent predictor of poor outcome and failure of hormone therapy. To understand further the function of AP‐2γ in breast carcinoma, we have used an RNA interference and gene expression profiling strategy with the MCF‐7 cell line as a model. Gene expression changes between control and silenced cells implicate AP‐2γ in the control of cell cycle progression and developmental signalling. A function for AP‐2γ in cell cycle control was verified using flow cytometry: AP‐2γ silencing led to a partial G1/S arrest and induction of the cyclin‐dependent kinase inhibitor, p21cip/
CDKN1A
. Reporter and chromatin immunoprecipitation assays demonstrated a direct, functional interaction by AP‐2γ at the
CDKN1A
proximal promoter. AP‐2γ silencing coincided with acquisition of an active chromatin conformation at the
CDKN1A
locus and increased gene expression. These data provide a mechanism whereby AP‐2γ overexpression can promote breast epithelial proliferation and, coupled with previously published data, suggest how loss of oestrogen regulation of AP‐2γ may contribute to the failure of hormone therapy in patients.