Mutant p53 Drives Invasion by Promoting Integrin Recycling

Abstract

p53 is a tumor suppressor protein whose function is frequently lost in cancers through missense mutations within the Tp53 gene. This results in the expression of point-mutated p53 proteins that have both lost wild-type tumor suppressor activity and show gain of functions that contribute to transformation and metastasis. Here, we show that mutant p53 expression can promote invasion, loss of directionality of migration, and metastatic behavior. These activities of p53 reflect enhanced integrin and epidermal growth factor receptor (EGFR) trafficking, which depends on Rab-coupling protein (RCP) and results in constitutive activation of EGFR/integrin signaling. We provide evidence that mutant p53 promotes cell invasion via the inhibition of TAp63, and simultaneous loss of p53 and TAp63 recapitulates the phenotype of mutant p53 in cells. These findings open the possibility that blocking alpha5/beta1-integrin and/or the EGF receptor will have therapeutic benefit in mutant p53-expressing cancers.

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

“…Mutant p53 drives invasion and metastasis through inactivation of targets such as p63 (5,6), ablating the p63 signalling pathways responsible for the suppression of invasion and metastasis.…”

“…As such, a gain-of-function mutation in the TP53 gene would act as a double-edged sword to activate miR-155 levels through both a loss of wild-type p53-mediated repression and also through the inactivation of p63-mediated repression as a result of the oncogenic activities of mutant p53 (5,6). Findings from Adorno et al suggest that the presence of TGF-β is a critical factor for mutant p53 to sequester p63 from its target genes.…”

“…In particular, mutant p53 has been shown to acquire the ability to sequester p63 and p73, and this is thought to promote tumor invasion and metastasis (5,6). So what are the key downstream target genes of p63 and p73 that are deregulated to promote tumor progression in cancer cells expressing mutant p53?…”

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

“…As a consequence, the cells may become more resistant to further cycles of genotoxic therapy (Blandino et al, 1999;Bush and Li, 2002). Mutant p53 gain of function would also include cell spread, invasion and metastasis (Heinlein et al, 2008;Adorno et al, 2009;Muller et al, 2009;Wang et al, 2009). Although difficult to prove, the possibility of enhanced tumor progression should be taken into consideration.…”

“…In addition, accumulating evidence suggests that mutant p53 can function in an oncogenic manner, through a gain of function. The consequences of mutant p53 accumulation include increased chemoresistance and enhanced ability to metastasize Lang et al, 2004;Di Agostino et al, 2006;Strano et al, 2007;Muller et al, 2009). Thus, the accumulation of mutant p53 can be regarded as a major contribution to tumor progression.…”