A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.
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.
Department of Histology, Microbiology and Medical Biotechnologies, University of Padua School of Medicine, viale Colombo 3, 35100 Padua, Italy.
Maddalena
M
Adorno
Michelangelo
M
Cordenonsi
Marco
M
Montagner
Sirio
S
Dupont
Christine
C
Wong
Byron
B
Hann
Aldo
A
Solari
Sara
S
Bobisse
Maria Beatrice
MB
Rondina
Vincenza
V
Guzzardo
Anna R
AR
Parenti
Antonio
A
Rosato
Silvio
S
Bicciato
Allan
A
Balmain
Stefano
S
Piccolo
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051785:Smad Proteins / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D051785:Smad Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D018631:ras Proteins