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• W2017453661 abstract "EMSY is a gene amplified in 13-18% of breast and ovarian cancers, and encodes a protein reported to be a binding partner for BRCA2, that when overexpressed causes impairment of BRCA2 functions and so might constitute a mechanism for BRCA2 inactivation in non-hereditary breast and ovarian cancers. We hypothesised that if EMSY amplification abrogates BRCA2 function, cells harbouring EMSY gene amplification could have an impaired ability to elicit competent homologous recombination (HR) DNA repair in the presence of DNA double strand breaks (DSBs) and thus an increased sensitivity to DNA cross-linking agents and PARP inhibitors. EMSY amplification may therefore constitute a biomarker for response to these therapies. 59 cell lines were subjected to microarray based comparative genomic hybridisation (aCGH) with a resolution of 50Kb. Ten cell lines harbouring EMSY amplification were identified. These cell lines were matched by anatomical site and biomarker expression with cell lines lacking EMSY gene amplification. In addition, CAPAN1 (BRCA2 mutant), MDAMB436 and SUM149 (BRCA1 mutant) cells were included as controls. The associations between EMSY copy number, mRNA and protein expression were determined by aCGH and fluorescence in situ hybridisation, quantitative real-time PCR and western blotting respectively. Cell viability was assessed following transfection with validated short interfering RNAi (siRNA) against EMSY. Formation of foci of phosphorylated H2AX (γH2AX), a surrogate marker of the presence of double strand breaks, and RAD51, a surrogate marker of competent HR DNA repair, were assessed in cell lines with and without EMSY gene amplification following 10Gy of ionising radiation and treatment with cisplatin or the PARP inhibitor olaparib. Cell viability following treatment with cisplatin or olaparib was assessed to determine sensitivity of cell lines with and without EMSY amplification. EMSY is not consistently overexpressed at the mRNA and protein levels in cancer cells harbouring EMSY gene amplification. No significant difference in viability was seen in cells with or without EMSY amplification following silencing of EMSY using siRNA. Cell lines with EMSY amplification were able to elicit RAD51 foci formation in the presence of DNA double strand breaks, and did not differ from cancer cells devoid of EMSY amplification in their sensitivity to cisplatin and olaparib. These cells also showed a lower sensitivity to these drugs than CAPAN1, MDA-MB436 and SUM149 cells. EMSY amplification is not associated with an impairment of cancer cells to elicit RAD51 foci formation in the presence of DNA double strand breaks and is not associated with increased sensitivity to cisplatin or olaparib. Its potential use as a biomarker for response to cisplatin and PARP inhibitors should therefore be viewed with caution. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2011-3917" @default.
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• W2017453661 date "2011-04-15" @default.
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• W2017453661 title "Abstract 3917: EMSY amplification and overexpression is not associated with defective homologous recombination and does not predict sensitivity to cisplatin or PARP inhibitors" @default.
• W2017453661 doi "https://doi.org/10.1158/1538-7445.am2011-3917" @default.
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