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The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.

ABSTRACT: Tumor suppressor p53 is critical for suppressing all types of human cancers, including breast cancer. The p53 gene is somatically mutated in over half of all human cancers. The majority of the p53 mutations are missense mutations, leading to the expression of the full-length p53 mutants. Several hotspot mutations, including R175H, are frequently detected in human breast cancer. P53 cancer mutants not only lose tumor suppression activity but, more problematically, also gain new oncogenic activities. Despite correlation of the expression of p53 cancer mutants and the poor prognosis of human breast cancer patients, the roles of p53 cancer mutants in promoting breast cancer remain unclear. We used the humanized p53 cancer mutant knock-in (R175H) mice and mouse mammary tumor virus (MMTV)-Wnt-1 transgenic (mWnt-1) mice to specifically address the gain of function of R175H in promoting breast cancer. Although both R175H/R175HmWnt-1(R175HmWnt-1) and p53(-/-)mWnt-1 mice died from mammary tumor at the same kinetics, which was much earlier than mWnt-1 mice, most of the R175HmWnt-1 mice developed multiple mammary tumors per mouse, whereas p53(-/-)mWnt-1 and mWnt-1 mice mostly developed one tumor per mouse. The multiple mammary tumors arose in the same R175HmWnt-1 mouse exhibited different histological characters. Moreover, R175H gain-of-function mutant expands the mammary epithelial stem cells (MESCs) that give rise to the mammary tumors. As ATM suppresses the expansion of MESCs, the inactivation of ATM by R175H in mammary epithelial cells (MECs) could contribute to the expansion of MESCs in R175HmWnt-1 mice. These findings provide the basis for R175H to promote the initiation of breast cancer by expanding MESCs.

SUBMITTER: Lu X

PROVIDER: S-EPMC3586389 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.

Lu X X Liu D P DP Xu Y Y

Oncogene 20120723 23

Tumor suppressor p53 is critical for suppressing all types of human cancers, including breast cancer. The p53 gene is somatically mutated in over half of all human cancers. The majority of the p53 mutations are missense mutations, leading to the expression of the full-length p53 mutants. Several hotspot mutations, including R175H, are frequently detected in human breast cancer. P53 cancer mutants not only lose tumor suppression activity but, more problematically, also gain new oncogenic activiti ...[more]

PMID: 22824795

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Project description:Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

Dataset Information

The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.

Publications

The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.

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