Complexes formed by mutant p53 and their roles in breast cancer

Abstract

Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation.

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

“…CHEK2, a serine/threonine kinase, is activated upon DNA damage and implicated in pathways governing DNA repair, cell cycle arrest or apoptosis in response to the initial damage (Apostolou and Papasotiriou, 2017). TP53 is the most frequent mutational target in human cancers, and mutations in TP53 are associated with different types of malignancies and adverse prognoses, including during breast cancer (Bellazzo et al, 2018).…”

Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer

“…The functional p53 pathway prevents tumor development and growth; therefore, the p53 gene is mutated in most of the tumors (Mantovani et al, 2019). The "gain of function" mutation which prompt tumor cells to grow, metastasize, and resist therapies is one of the most common mutations in P53 genes (Bellazzo et al, 2018). Tp53 mutations (mutp53) are very common in PDAC (Muller and Vousden, 2014).…”

Gain-of-function mutant p53: history and speculation

“…The mechanism by which mtp53 activates transcription signatures is very likely through its interaction with transcription factors that recruit the mtp53 GOF proteins to pro-survival targets (reviewed in Freed-Pastor and Prives, 2012; Muller and Vousden, 2013, 2014; Aschauer and Muller, 2016; Bellazzo et al, 2018; Kim and Lozano, 2018). One hypothesis is that once recruited to a given transcription factor that itself is bound to specific sequences in its target genes, mtp53 can contribute to the transcription of these targets by dint of the potent p53 transcriptional activation domain (TAD).…”