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Title: ZNF703 is a luminal-breast-cancer oncogene
Author: Holland, D.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2011
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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 ZNF703 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 ZNF703 expression altered transcription of genes including TGFBR2, which are also found in an expression signature of ZNF703 amplification in a dataset of 1001 breast tumours. ZNF703 was also found to bind to the promoter of TGFBR2, and to alter recruitment of chromatin modifying enzymes HDAC1 and p300. Overexpression of ZNF703 rendered MCF-7 cells insensitive to TGFβ-induced suppression of mammosphere formation. Finally, forced overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together these data strongly suggest that ZNF703 is a novel oncogene in luminal B breast cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available