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• W2034096465 abstract "The emergence of drug resistant tumours that are able to escape cell death pose a major problem in the treatment of cancers. Tumours develop resistance to DNA-damaging chemotherapeutic agents by acquiring the ability to repair their DNA. Combination therapies that induce DNA damage and disrupt the DNA damage repair process may therefore prove to be more effective against such tumours. The developmentally important transcription factor TBX2 has been suggested as a novel anticancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferative functions. Importantly, we recently showed that when TBX2 is silenced, we are able to reverse several features of transformation in both breast cancer and melanoma cells. Overexpression of TBX2 has also been linked to drug resistance and we have shown that its ectopic expression results in genetically unstable polyploidy cells with resistance to cisplatin. Whether the overexpression of endogenous TBX2 levels is associated with cisplatin resistance in TBX2-driven cancers has, however, not been shown. To address this we have silenced TBX2 in a cisplatin-resistant breast cancer cell line and we show that knocking down TBX2 sensitises the cells to cisplatin by disrupting the ATM-CHK2-p53 signalling pathway. Cell cycle analyses demonstrate that when TBX2 is knocked down there is an abrogation of an S-phase arrest but a robust G2/M arrest that correlates with a reduction in phosphorylated CHK2 and p53 levels. This prevents DNA repair resulting in TBX2-deficient cells entering mitosis with damaged DNA and consequently undergoing mitotic catastrophe. These results suggest that targeting TBX2 in combination with chemotherapeutic drugs such as cisplatin could improve the efficacy of current anticancer treatments." @default.
• W2034096465 created "2016-06-24" @default.
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• W2034096465 date "2013-10-10" @default.
• W2034096465 modified "2023-10-09" @default.
• W2034096465 title "A novel role for the anti-senescence factor TBX2 in DNA repair and cisplatin resistance" @default.
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• W2034096465 doi "https://doi.org/10.1038/cddis.2013.365" @default.
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