AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene.
Overexpression of the activator protein (AP)-2gamma 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-2gamma 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-2gamma in the control of cell cycle progression and developmental signalling. A function for AP-2gamma in cell cycle control was verified using flow cytometry: AP-2gamma 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-2gamma at the CDKN1A proximal promoter. AP-2gamma silencing coincided with acquisition of an active chromatin conformation at the CDKN1A locus and increased gene expression. These data provide a mechanism whereby AP-2gamma overexpression can promote breast epithelial proliferation and, coupled with previously published data, suggest how loss of oestrogen regulation of AP-2gamma may contribute to the failure of hormone therapy in patients.
Barts & The London School of Medicine and Dentistry, Queen Mary University of London, Centre for Tumour Biology, Institute of Cancer, Charterhouse Square, London, UK.
Christopher M J
CM
Williams
Angelo G
AG
Scibetta
J Karsten
JK
Friedrich
Monica
M
Canosa
Chiara
C
Berlato
Charlotte H
CH
Moss
Helen C
HC
Hurst
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D050656:Transcription Factor AP-2 / Q000502:physiology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050656:Transcription Factor AP-2