Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Mutations in the p53 tumor suppressor gene can lead to a gain of function, promoting cancer progression, metastasis, and centrosome abnormalities.
• These abnormalities include centrosome amplification, increased size, and loss of cohesion, resulting in mitotic defects and multinucleation.

Purpose of the Study:

• To identify endogenous proteins that can specifically target and suppress the oncogenic functions of mutant p53.
• To investigate the role of ANKRD11 in regulating the oncogenic potential of mutant p53 in cancer cells.

Main Methods:

• Inducible expression of p53 hotspot mutants in cells.
• Assessment of centrosome abnormalities, mitotic defects, and cellular morphology.
• Evaluation of invasive capabilities and mesenchymal-like transformation.
• Analysis of ANKRD11 expression in breast cancer patient data.
• Mechanistic studies involving p53 conformation and protein complex dissociation.

Main Results:

• Expression of mutant p53 induced centrosome abnormalities, mitotic defects, altered morphology, and enhanced invasion.
• Loss of ANKRD11 expression correlated with p53 mutation and poor prognosis in breast cancer patients.
• ANKRD11 suppressed mutant p53-driven mitotic defects, invasion, and mesenchymal-like transformation.
• ANKRD11 restored native conformation to mutant p53 and dissociated the mutant p53-p63 complex.

Conclusions:

• ANKRD11 acts as a key regulator suppressing the oncogenic functions of mutant p53.
• ANKRD11 represents a novel therapeutic target for cancers harboring p53 mutations.
• The findings provide the first evidence of an endogenous protein capable of suppressing mutant p53's oncogenic properties.