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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage
Luiza Steffens Reinhardt1,2, Xiajie Zhang1,2, Kira Groen1,2
1School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia.
Abstract:
Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high ∆40p53:p53α ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Δ40p53 and p53α levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was investigated in vitro. Our results revealed that a high Δ40p53:p53α ratio causes cells to respond differently to doxorubicin and cisplatin treatments. Δ40p53 overexpression significantly impairs the cells' sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas Δ40p53 knockdown has the opposite effect. Further, a high Δ40p53:p53α ratio inhibited the differential expression of several genes following doxorubicin and promoted DNA repair, impairing the cells' canonical response. Overall, our results suggest that the response of breast cancer cells to standard of care DNA-damaging therapies is dependent on the expression of p53 isoforms, which may contribute to outcomes in breast cancer.
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