Poster Presentation 35th Lorne Cancer Conference 2023

The p53 C-terminal variant, p53β, is associated with worse survival outcomes in melanoma and breast cancer. (#329)

Luiza Steffens Reinhardt 1 2 , Kira Groen 1 3 , Jean-Christophe Bourdon 4 , Kelly Avery-Kiejda 1 2
  1. School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
  2. Cancer Detection & Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  3. Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  4. Dundee Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom

Background: In breast cancer and melanoma TP53’s overall mutation frequency is much lower than expected, suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms can modulate p53 pathway activity and our previous studies revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer1,2 and with chemotherapy response in melanoma3. However, due to a lack of specific antibodies, it has not been possible to define their endogenous protein expression patterns and localisation in tissues.

Aim: To define the protein expression and localisation of p53 isoforms in breast cancer and melanoma; and establish their relationship with clinicopathological and prognosis.

Methods: p53 isoform expression (transactivation domain p53 – TAp53, p53β, ∆40p53, ∆133p53, ∆160p53) was evaluated in 108 breast cancer4 and 123 melanoma specimens by immunohistochemistry using a suite of novel p53 isoform specific antibodies.

Results: p53 isoforms were predominantly expressed in the nucleus, but cytoplasmic localisation was also observed. The expression of p53 isoforms varied considerably amongst specimens but was generally lower in breast cancer compared to melanoma. In breast cancer, p53β was the highest expressed p53 isoform, apart from the TAp53 and high levels of cytoplasmic p53β isoforms were significantly associated with worse disease-free survival when compared to specimens expressing low levels (p=0.013)4. In melanoma, p53β was the highest expressed p53 isoform and elevated p53β expression correlated with reduced probability of melanoma specific survival (p<0.001), while Δ40p53 expression positively correlated with less advanced melanoma (p=0.013). Elevated expression of TAp53 was associated with worse survival outcomes and more advanced stages of cancer.

Conclusions: This is the first study to investigate endogenous levels of p53 isoform protein expression in breast cancer and melanoma. We showed that p53 isoforms can be detected using a suite of C- and N-terminal p53 isoform specific antibodies. Both p53β and TAp53 were found to harbour prognostic biomarker potential in these diseases.

  1. Morten BC, Wong-Brown MW, Scott RJ and Avery-Kiejda KA. The presence of the intron 3 16bp duplication polymorphism of p53 (rs17878362) in breast cancer is associated with a low ∆40p53:p53 ratio and better outcome. Carcinogenesis 2016; 37(1): 81-6. doi: 10.1093/carcin/bgv164.
  2. Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A and Scott RJ. The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome. Carcinogenesis 2014; 35(3), 586-596. doi:10.1093/carcin/bgt411
  3. Avery-Kiejda KA, Zhang XD, Adams LJ, Scott R, Vojtesek B, Lane DP and Hersey P. Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin. Clinical Cancer Research 2008; 14(6), 1659-1668. doi:10.1158/1078-0432.ccr-07-1422
  4. Steffens Reinhardt L, Groen K, Morten BC, Bourdon JC, and Avery-Kiejda KA. Cytoplasmic p53β isoforms are associated with worse disease-free survival in breast cancer Int. J. Mol. Sci. 2022, 23, 6670. https://doi.org/10.3390/ijms23126670