Poster Presentation NSW State Cancer Conference 2023

The Link Between Aberrations in the p53 Pathway and Outcomes from DNA-Damaging Therapies in Breast Cancer (#147)

Luiza Steffens Reinhardt 1 2 , Kira Groen 1 , Xiajie Zhang 1 2 , Alexandre Xavier 1 , Brianna Morten 1 , Jean-Christophe Bourdon 3 , Kelly Avery-Kiejda 1 2
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
  2. Cancer Detection & Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  3. Dundee Cancer Centre, Ninewells Hospital and Medical School, The University of Dundee, Dundee, UK

DNA-damaging therapies trigger apoptosis via the p53 pathway and are frequently used in breast cancer treatment. TP53 is often mutated in cancers, yet, TP53 pathogenic mutations are detected in ~25% of breast cancers and hence, other mechanisms may affect the activities of this important tumour suppressor. This study focused on characterising the molecular alterations in the p53 pathway that result in DNA-damaging therapies resistance, in particular, p53 isoforms which may be associated with worse breast cancer-free survival1,2.

By using overexpression and knockdown in vitro3 and in vivo models, we demonstrated that altered levels of the N-terminally truncated p53 isoform, Δ40p53, impact the response to DNA-damaging agents used in breast cancer treatment and cellular differentiation state. Endogenously, Δ40p53 is highly expressed in a cell subpopulation with stem-like features and Δ40p53 levels are associated with enhanced pluripotency4. Following doxorubicin, Δ40p53 prevents p53 canonical DNA damage response (DDR) and apoptosis, impairs p53’s regulation of DNA double-strand break repair, and contributes to chemoresistance5. Δ40p53 knockdown had the opposite effect, suggesting that targeting Δ40p53 in breast cancer may enhance the efficacy of standard-of-care therapies such as doxorubicin. To infer aberrant activity of cellular pathways in tumours with high or low ∆40p53 expression, cDNA microarray data of 64 invasive ductal carcinomas (IDCs) were reanalysed and the results strongly indicate that a high Δ40p53:p53 ratio significantly affects breast cancer cell fate decisions and that p53 functions in breast cancer are modulated by the levels of the Δ40p53 isoform4,5.

Although p53 isoform activities contribute to p53 dysregulation, p53 isoform expression is not expected to be responsible for all p53 malfunction in breast cancer. With the imperative roles of the p53 pathway in the DDR, genetic alterations in DDR genes were evaluated in a cohort of 137 therapy-naïve IDCs by targeted next-generation sequencing. Novel mutations in several genes were discovered, resulting in a substantial mutation burden. Mutations in PARP1 and ATR predicted worse breast cancer-free survival, especially for patients who received chemotherapies, indicating the status of these genes may be promising biomarkers to guide the selection of patients most likely to benefit from therapies that target these genes or pathways they are involved in. Overall, our results provide important insights into the p53 dysregulation in breast cancer and suggest promising therapeutic targets and prognostic markers associated with the p53 pathway. Future work envisages translating these findings to clinical approaches, providing guidance for treatment decisions and improving breast cancer outcomes.

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  2. 2.International Journal of Molecular Sciences 2022; 23(12), 6670; doi: 10.3390/ijms23126670
  3. 3.Molecular Oncology 2021, 16, 447-465. doi: 10.1002/1878-0261.13118
  4. 4.Research Square Preprint 2023. doi: 10.21203/rs.3.rs-2536787/v1
  5. 5.Cell Death and Disease 2022; 13(10):907. doi: 10.1038/s41419-022-05349-9