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

摘要

TGFβ ligands act as tumor suppressors in early stage tumors but are paradoxically divertedinto potent prometastatic factors in advanced cancers. The molecular nature of this switchremains enigmatic. Here we show the workings of a previously undescribed pathway in whichTGFβ-dependent cell migration, invasion and metastasis are empowered by mutant-p53 andopposed by p63. Mechanistically, TGFβ acts in concert with oncogenic Ras and mutant-p53 toinduce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essentialplatforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63,we identified two novel metastasis suppressor genes associated with metastasis risk in a largecohort 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-upwith particular metastasis proclivity by TGFβ-dependent inhibition of p63 function.