TY - JOUR
T1 - Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage
AU - Steffens Reinhardt, Luiza
AU - Zhang, Xiajie
AU - Groen, Kira
AU - Morten, Brianna C.
AU - De Iuliis, Geoffry N.
AU - Braithwaite, Antony W.
AU - Bourdon, Jean-Christophe
AU - Avery-Kiejda, Kelly A.
N1 - Funding Information:
The authors would like to express their gratitude for the financial support of The Hunter Medical Research Institute and The University of Newcastle. Luiza Steffens Reinhardt is supported by a University Postgraduate Award. XZ is supported by University Postgraduate Award and a Hunter Cancer Research Alliance PhD Scholarship. KAAK is supported by the Cancer Institute NSW (Career Development Fellowship; CDF181205).
Copyright:
© The Author(s) 2022.
PY - 2022/10/28
Y1 - 2022/10/28
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Breast cancer
KW - DNA damage and repair
UR - http://www.scopus.com/inward/record.url?scp=85140629793&partnerID=8YFLogxK
U2 - 10.1038/s41419-022-05349-9
DO - 10.1038/s41419-022-05349-9
M3 - Article
C2 - 36307393
SN - 2041-4889
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - 907
ER -
