Contribution of p53 to Metastasis

Abstract

The tumor suppressor p53 is lost or mutated in about half of all human cancers and in those tumors where it is wild-type, mechanisms exist to prevent its activation. p53 loss not only prevents incipient tumor cells from undergoing oncogene-induced senescence and apoptosis but also perturbs cell cycle checkpoints. This enables p53-deficient tumor cells with DNA damage to continue cycling, creating a permissive environment for the acquisition of additional mutations. Theoretically, this could contribute to the evolution of a cancer genome that is conducive to metastasis. Importantly, p53 loss also results in the disruption of pathways that inhibit metastasis, and transcriptionally defective TP53 mutants are known to gain additional functions that promote metastasis. Here, we review the evidence supporting a role for p53 loss or mutation in tumor metastasis, with an emphasis on breast cancer.

Proteome-wide analysis of mutant p53 targets in breast cancer identifies new levels of gain-of-function that influence PARP, PCNA, and MCM4

“…Knowledge of the proteome diversity driven by mtp53 suggests that DNA replication and repair pathways are major targets of mtp53 and highlights consideration of combination chemotherapeutic strategies targeting cholesterol biosynthesis and PARP inhibition. T he cellular response to mutations in the p53 gene and to stable expression of mutant p53 (mtp53) protein in breast cancer is increasingly accepted as an oncogenic signal transducer (1)(2)(3)(4)(5)(6). The Cancer Genome Atlas Project identified TP53 mutations in 12% of luminal A, 32% of luminal B, 84% of basallike, and 75% of HER2-expressing breast cancers (6).…”

“…Many TP53 mutations are missense changes that cause a change in a single amino acid residue most often found in the central site-specific DNA binding domain, but the mutations cause variable changes that range from loss to gain of function (2,4). Although some TP53 mutations contribute to breast cancer metastasis because of loss of p53 tumor suppressor activity, many missense TP53 mutations cause newfound gain-offunction oncogenic activities to the mtp53 protein that range from activation of tumor-promoting target genes to the inhibition of p53 family members p63 and p73 (5). This gain of function is associated with mtp53 protein that often has a prolonged t 1/2 and is highly expressed in cancer cells (8,9).…”

“…This gain of function is associated with mtp53 protein that often has a prolonged t 1/2 and is highly expressed in cancer cells (8,9). The predominant mode of mtp53-mediated regulation has been described as activation and repression of gene transcription (2,4,5,10).…”

“…Primary "hotspot" residues for mutation in the p53 393-aa protein found in human cancers are R175, G245, R248, R249, R273, and R282 (2,4,5). Mouse models knocked in for expressing the mtp53 equivalents to human R175H and R273H demonstrate gain of function (compared with mice without p53, or with WT p53) by displaying more metastatic tumors (11,12).…”

Evaluation of Genotoxicity of Lufenuron and Chlorfluazuron Insecticides in Drosophila melanogaster Using a Germ-Line Cell Aneuploidy and Chromosomal Aberrations Test

“…DNA damage resulting from genotoxic stress triggers transcription of genes that limit mutations and promote survival in organisms ranging from bacteria to humans [36]. These are the tumor suppressor genes (TSGs) in which a lossof-function mutation leads to cellular overproliferation [37].…”