Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage

Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high increment 40p53:p53 alpha ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Delta 40p53 and p53 alpha 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 Delta 40p53:p53 alpha ratio causes cells to respond differently to doxorubicin and cisplatin treatments. Delta 40p53 overexpression significantly impairs the cells' sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas Delta 40p53 knockdown has the opposite effect. Further, a high Delta 40p53:p53 alpha 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.

Automated summary

This study found that the response of breast cancer cells to DNA-damaging therapies in standard care is dependent on the expression of p53 isoforms. A high Delta 40p53:p53 alpha ratio causes cells to respond differently to doxorubicin and cisplatin treatments, increasing resistance to doxorubicin and promoting DNA repair, thereby impairing the cells' normal response.