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 in which 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.

Significance: The metastatic potential of tumor cells can be positively infl uenced by loss of p53 or expression of p53 gain-of-function mutants. Understanding the mechanisms by which p53 loss and mutation promote tumor metastasis is crucial to understanding the biology of tumor progression and how to appropriately apply targeted therapies.

Figure 1. p53 loss affects several steps of the metastatic process

The loss of oncogene-induced senescence and apoptosis that results from the loss of p53 allows tumors to be established. The loss of checkpoint control enables p53-deficient tumors 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 (step 1). The loss of p53 results in gene expression changes (see Table 1) in tumor cells, leading to the acquisition of invasion properties that enable tumor cells to breach the ECM, undergo EMT, and acquire migratory capabilities (step 2). Altered invasive and migratory properties allow tumor cells to intravasate neighboring blood vessels, and loss of anoikis enables tumor cells to survive detachment from the ECM (step 3). Altered invasive and migratory properties allow tumor cells to extravasate into the secondary (metastatic) site (step 4) and proliferate (step 5).

Figure 2. Metastasis pathways that affect, or are affected by, p53

p53 regulates the transcription of genes that are involved in pathways that negatively regulate tumor metastasis. The key pathways and pathway components in the metastatic cascade that are regulated by or converge on p53 are grouped according to color.