A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis

Abstract

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

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?…”

“…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? Recent studies have identified the metastasis suppressors SHARP1 and cyclin G2 as critical mutant p53 targets that are deregulated through loss of p63 signalling (6). The expression of these two genes alone defined a subset of particularly aggressive breast tumors associated with poor patient outcome (6).…”

“…Recent studies have identified the metastasis suppressors SHARP1 and cyclin G2 as critical mutant p53 targets that are deregulated through loss of p63 signalling (6). The expression of these two genes alone defined a subset of particularly aggressive breast tumors associated with poor patient outcome (6). Such examples demonstrate the potential utility of targets of mutant p53 as robust clinical prognostic tools and therapeutic targets in mutant p53 expressing tumors, however a complete understanding of the mechanisms and pathways exploited by mutant p53 to drive tumorigenesis remain poorly understood.…”