Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage.
Luiza Steffens ReinhardtXiajie ZhangKira GroenBrianna C MortenGeoffry N De IuliisAntony W BraithwaiteJean-Christophe BourdonKelly A Avery-KiejdaPublished in: Cell death & disease (2022)
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.
Keyphrases
- dna damage
- dna repair
- cell cycle arrest
- induced apoptosis
- oxidative stress
- cell death
- endoplasmic reticulum stress
- healthcare
- drug delivery
- poor prognosis
- free survival
- palliative care
- breast cancer cells
- single molecule
- pi k akt
- cancer therapy
- metabolic syndrome
- gene expression
- quality improvement
- pain management
- skeletal muscle
- long non coding rna
- high resolution
- health insurance
- mass spectrometry
- weight loss
- childhood cancer
- atomic force microscopy