p53 Targeted Therapies in Triple Negative Breast Cancer

The objective of this review is to discuss the mechanisms of oncogenicity of somatic TP53 mutations in triple negative breast cancer and the targeted therapies aiming to improve prognosis and outcome for these aggressive cancers. Mutant p53 proteins demonstrate loss of function, gain of function, and dominant negative effects on wild-type p53 proteins contributing to more advanced and aggressive disease and poor clinical outcomes, particularly in triple negative breast cancer. The immunogenicity of triple negative breast cancer renders it an attractive subject of investigation into the molecular mechanisms of the tumor microenvironment. Although there are no clinically-available p53-directed targeted therapies at present, several mechanisms of oncogenicity are under preclinical and clinical study as promising targets for new treatment strategies. The mechanisms that have yielded the most results are conformational rescue, prevention of aggregation, promotion of degradation, cell cycle inhibition, vector therapy, and immunotherapy. These targeted therapies have the potential to restore wild-type p53 tumor suppressor function and reverse the immunogenic tumor microenvironment that is characteristic of triple negative breast cancer. There are multiple targeted therapies in the clinical and preclinical stage of investigation that may restore wild-type p53 tumor suppressor function and improve clinical outcomes in patients with triple negative breast cancer expressing a somatic TP53 mutation.