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

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 (similar to 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), p53 beta, Delta 40p53, Delta 133p53 and Delta 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 p53 beta, most likely to be N-terminally truncated beta 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 p53 beta may be a useful prognostic marker.

Automated summary

TP53 mutations are associated with tumor progression, therapy resistance, and poor prognosis in breast cancer. However, other mechanisms, such as p53 isoform dysregulation, may contribute to the disruption of the p53 pathway. This study found that high levels of p53 beta, a N-terminally truncated variant, were significantly associated with worse disease-free survival, especially in tumors with wild-type TP53, suggesting that p53 beta may serve as a prognostic marker in breast cancer.