Role of p53 Gene in Breast Cancer: Focus on Mutation Spectrum and Therapeutic Strategies

Abstract

TP53 is a tumor suppressor gene which is commonly mutated in various cancers including breast cancer. Alterations in the gene lead to an altered expression of various genes that are directly or indirectly under the transcriptional control of p53. This results in malfunctioning of DNA damage repair pathways, cell-cycle arrest, chromatin remodeling and apoptosis. Different mutations in TP53 gene have been reported in different ethnic groups and exon 4 and intron 3 are reported to be frequently mutated in breast cancer patients especially triplenegative breast cancer. Increased global burden of TP53 mutated breast tumors has paved the path for various therapies targeting p53/TP53. Numerous molecules including nutilins, MI series, RO5693, PRIMA-1, RITA, etc. have been developed. Majority of these restore p53/TP53 function by targeting negative regulators of p53/TP53, wtp53/TP53 (wild-type) and mtp53/TP53 (mutant). Most of these molecules are in the preclinical phase except for two APR-246 and COTI-2 that have progressed to clinical trials. The current review has been compiled with an aim to give an overview of mutations in p53 across various ethnic groups, the effect of these alterations on TP53 function and the therapeutic strategies developed till date targeting p53/TP53 especially in breast cancer.

Identification of the potential roles of ring finger protein 8 in TP53‑mutant breast cancer

“…The present study identified the differentially expressed genes in mouse transcriptome data from the GEO database by comparing the low and normal expression levels of RNF8 in the TP53-mutant samples, revealing that downregulated genes were mainly enriched in several pathways involved in cell proliferation and apoptosis regulation, development and transcription regulation. This is consistent with previous studies (28,29), indicating that even in the presence of P53 mutations, the main function of RNF8 is still focused on the regulation of the cell cycle and transcription factors, thus confirming that the function of RNF8 is not completely P53-dependent and that TP53 mutations have a relatively small effect on the physiological function of RNF8.…”

“…A previous study has revealed that the function of RNF8 is highly dependent on the P53 protein, suggesting that RNF8 serves a biological role in synergy with P53 (27). However, numerous studies have revealed a number of mutations in the P53 gene in tumor cells (28,29); therefore, it is increasingly important to investigate the functional role of RNF8 under the condition of P53 mutation (27). The present study identified the differentially expressed genes in mouse transcriptome data from the GEO database by comparing the low and normal expression levels of RNF8 in the TP53-mutant samples, revealing that downregulated genes were mainly enriched in several pathways involved in cell proliferation and apoptosis regulation, development and transcription regulation.…”

p.Arg72Pro polymorphism of P53 and breast cancer risk: a meta-analysis of case-control studies

“…It should be noted that the incidence of breast cancer differs among different populations around the world [ 1 ]. Over the past decades, major advances have been made in understanding the pathology of breast cancer at the molecular level, including the involvement of certain genes associated with the development of the disease such as BRCA1 , BRCA2 and P53 which produce tumor suppressor proteins and participate in damaged DNA repair [ 3 – 5 ]. P53 plays a key role in the regulation of cell proliferation and apoptosis.…”

Prognostic and clinical significance of focal adhesion kinase expression in breast cancer: A systematic review and meta-analysis

“…The present results also demonstrate that increased FAK protein expression correlates with a high Ki-67 expression level, thereby suggesting that elevated FAK expression promotes the proliferation of breast cancer cells. Kaur et al [ 44 ] have revealed that p53 also contributes to the pathogenesis of breast cancer via its roles in various cellular processes, including DNA damage repair, cell cycle arrest, and apoptosis. The present results demonstrate that enhanced FAK expression correlates with positive p53 status.…”