Abstract
Mutant p53 enhances cancer cell invasion in response to inflammatory cytokines such as TNFα.
Major finding: Mutant p53 enhances cancer cell invasion in response to inflammatory cytokines such as TNFα.
Mechanism: Cytoplasmic interaction between mutant p53 and DAB2IP sustains NFκB activation and inhibits JNK.
Impact: Gain-of-function mutation of p53 reprograms inflammatory signaling to promote tumor progression.
Inflammation is recognized as a key factor in carcinogenesis; however, the precise mechanisms by which the immune response affects cancer development remain largely unknown. Mutation of the p53 tumor suppressor has been linked to a heightened proinflammatory microenvironment, prompting Di Minin, Bellazzo, and colleagues to study whether activation of inflammatory responses by mutant p53 is involved in driving cancer progression and metastasis. In support of this idea, silencing of mutant p53 in breast cancer cells inhibited cell migration and enhanced apoptosis in response to the proinflammatory cytokine TNFα. Transcriptional profiling revealed a set of TNFα-inducible NFκB target genes with proinvasive and immunogenic functions, which were regulated in a mutant p53–dependent manner. Intriguingly, chemical inhibition of pathways downstream of TNFα showed that, whereas the majority of genes were NFκB-dependent, inhibition of JNK upregulated a subset of genes specifically in cells depleted for mutant p53. Mechanistically, mutant p53, but not wild-type p53, sustained NFκB activation and inhibited JNK signaling in response to TNFα by interacting with the tumor suppressor disabled 2-interacting protein (DAB2IP) in the cytoplasm. In line with this finding, depletion of DAB2IP rescued TNFα-induced invasion of mutant p53–depleted cells and restored the proper phosphorylation kinetics of downstream TNF targets. Importantly, overexpression of DAB2IP or disruption of DAB2IP binding to mutant p53 inhibited cytokine-induced cell migration in vitro and reduced metastasis in vivo. Unexpectedly, analysis of gene expression data from triple-negative breast cancers revealed that a subset of the mutant p53/TNF gene signature correlated with prolonged disease-free survival and upregulation of immune-specific genes, suggestive of a proinflammatory phenotype polarized toward immune surveillance rather than tolerance. Together, this work provides evidence that mutant p53 modulates the TNF pathway via interaction with the signaling protein DAB2IP to promote a transcriptional program that favors cell invasion and specific inflammatory processes.
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