Role of p53 in breast cancer progression: An insight into p53 targeted therapy

The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.

Automated summary

The transcription factor p53 plays a crucial role in regulating cellular processes and is activated in response to genotoxic stress. In breast cancer, p53's tumor suppressive activities are often compromised by the overexpression of MDM2 or mutation, with the latter being more common in hormone receptor-negative patients. Targeting both wild-type and mutant p53 in different subtypes of breast cancer has potential clinical relevance, and various therapeutic strategies including small molecule inhibitors, peptides, PROTACs, and genetic-based approaches are being developed. This review highlights the ongoing efforts to overcome p53 inactivation in breast tumors and discusses the efficacy and limitations of these therapeutic strategies.