Altered Ratios of p53 Isoforms Predict Response of Breast Tumors to Chemotherapy

Alterations in the distribution of p53 isoforms are predictive of the likelihood that a breast tumor will respond to treatment with the chemotherapeutic drug doxorubicin.

The regulatory protein p53 is often mutated in human cancers. In vertebrates, the p53 protein complex is vital for prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.

Investigators at the Hunter Medical Research Institute (New Lambton Heights, Australia) have shown in previous studies that p53 isoform expression was altered in breast cancer and related to prognosis. In particular, a high delta40p53:p53alpha ratio was associated with worse disease-free survival.

In the current study, the influence of altered delta40p53 and p53alpha levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was evaluated.

Results revealed that a high delta40p53:p53alpha ratio caused cells to respond differently to doxorubicin and cisplatin treatments. Delta40p53 overexpression significantly impaired the cells’ sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas inhibition of delta40p53 had the opposite effect. Further, a high delta40p53:p53alpha ratio inhibited the differential expression of several genes following doxorubicin and promoted DNA repair.

Overall, these results suggested that the response of breast cancer cells to standard of care DNA-damaging therapies was dependent on the expression of p53 isoforms, which may contribute to outcomes in breast cancer.

Senior author Dr. Kelly Avery-Kiejda, associate professor of biomedical sciences and pharmacy at he Hunter Medical Research Institute, said, “One in eight women in Australia develop breast cancer and while there is a 92% survival rate, this does not take into account secondary cancers or metastasis, which are essentially incurable. If we can identify biomarkers that predict how well a patient will respond to certain therapies, we can then target the available therapies more effectively.”

The findings were published in the October 28, 2022, online edition of the journal Cell Death & Disease.

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