Cytoplasmic p53β Isoforms Are Associated with Worse Disease-Free Survival in Breast Cancer

TY - JOUR

T1 - Cytoplasmic p53β Isoforms Are Associated with Worse Disease-Free Survival in Breast Cancer

AU - Steffens Reinhardt, Luiza

AU - Groen, Kira

AU - Morten, Brianna C.

AU - Bourdon, Jean-Christophe

AU - Avery-Kiejda, Kelly A.

N1 - Funding Information: Funding: This work was funded by the Cancer Institute NSW and the Hunter Medical Research Institute. L.S.R. is supported by a University of Newcastle International Postgraduate Research Scholarship and a University of Newcastle Research Scholarship External. K.A.A.-K. is supported by the Cancer Institute NSW (Career Development Fellowship; CDF181205). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/6/15

Y1 - 2022/6/15

N2 - TP53 mutations are associated with tumour progression, resistance to therapy and poor prognosis. However, in breast cancer, TP53′s overall mutation frequency is lower than expected (~25%), suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms are known to enhance or disrupt p53 pathway activity in cell-and context-specific manners. Our previous study revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer and may account for the dysregulation of the p53 pathway in the absence of TP53 mutations. Hence, in this study, the protein expression of p53 isoforms, transactivation domain p53 (TAp53), p53β, ∆40p53, ∆133p53 and ∆160p53 was analysed using immunohistochemistry in a cohort of invasive ductal carcinomas (n = 108). p53 isoforms presented distinct cellular localisation, with some isoforms being expressed in tumour cells and others in infiltrating immune cells. Moreover, high levels of p53β, most likely to be N-terminally truncated β variants, were significantly associated with worse disease-free survival, especially in tumours with wild-type TP53. To the best of our knowledge, this is the first study that analysed the endogenous protein levels of p53 isoforms in a breast cancer cohort. Our findings suggest that p53β may be a useful prognostic marker.

AB - TP53 mutations are associated with tumour progression, resistance to therapy and poor prognosis. However, in breast cancer, TP53′s overall mutation frequency is lower than expected (~25%), suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms are known to enhance or disrupt p53 pathway activity in cell-and context-specific manners. Our previous study revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer and may account for the dysregulation of the p53 pathway in the absence of TP53 mutations. Hence, in this study, the protein expression of p53 isoforms, transactivation domain p53 (TAp53), p53β, ∆40p53, ∆133p53 and ∆160p53 was analysed using immunohistochemistry in a cohort of invasive ductal carcinomas (n = 108). p53 isoforms presented distinct cellular localisation, with some isoforms being expressed in tumour cells and others in infiltrating immune cells. Moreover, high levels of p53β, most likely to be N-terminally truncated β variants, were significantly associated with worse disease-free survival, especially in tumours with wild-type TP53. To the best of our knowledge, this is the first study that analysed the endogenous protein levels of p53 isoforms in a breast cancer cohort. Our findings suggest that p53β may be a useful prognostic marker.

KW - Breast Neoplasms/genetics

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Mutation

KW - Progression-Free Survival

KW - Protein Isoforms/genetics

KW - Tumor Suppressor Protein p53/metabolism

KW - breast cancer

KW - disease-free survival

KW - p53 isoforms

KW - ∆133p53β

KW - TP53 mutation status

UR - https://www.scopus.com/pages/publications/85131946993

U2 - 10.3390/ijms23126670

DO - 10.3390/ijms23126670

M3 - Article

C2 - 35743117

SN - 1661-6596

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 12

M1 - 6670

ER -