ZNF703 is a luminal-breast-cancer oncogene

• Main Author: Holland, D.
• Published: University of Cambridge 2011
• Subjects: 616.994
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604163

Amplification of the 8p11-12 is frequent in breast cancers and correlates with a poor prognosis. Four different cores of amplification have been identified and the most telomeric contains several putative oncogenes that show strong correlation between amplification and overexpression. This study identifies the <i>ZNF703</i> gene as the most likely driving oncogene of the most distal of these amplification cores. Firstly, this amplicon core is associated with ER positive breast cancer and more specifically occurs predominantly in the luminal B subtype. The minimal amplicon was found to include only the gene ZNF703 and to correlate with increased gene and protein expression. Amplification of this core was also found to be associated with poor outcome. In the luminal breast cancer cell line MCF-7, manipulation of <i>ZNF703</i> expression altered transcription of genes including TGFBR2, which are also found in an expression signature of <i>ZNF703</i> amplification in a dataset of 1001 breast tumours. ZNF703 was also found to bind to the promoter of <i>TGFBR2</i>, and to alter recruitment of chromatin modifying enzymes HDAC1 and p300. Overexpression of <i>ZNF703</i> rendered MCF-7 cells insensitive to TGFβ-induced suppression of mammosphere formation. Finally, forced overexpression of <i>ZNF703</i> in normal human breast epithelial cells enhanced the frequency of <i>in vitro</i> colony-forming cells from luminal progenitors. Taken together these data strongly suggest that <i>ZNF703</i> is a novel oncogene in luminal B breast cancer.