Mutant p53 elicits context-dependent pro-tumorigenic phenotypes.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• TP53 is a crucial tumor suppressor gene frequently mutated in various cancers, including prostate cancer (PCa).
• Missense mutations in TP53, particularly at the R273 hotspot, are enriched in PCa, with a specific preference for R273C-p53.
• TP53 mutations can occur with maintained heterozygosity or loss of heterozygosity (LOH), influencing p53 function.

Purpose of the Study:

• To investigate the functional consequences of specific TP53 mutations (R273C and R273H) in PCa.
• To model tumor-associated mutant p53 in the presence or absence of wild-type p53 to understand context-dependent effects.
• To elucidate the role of mutant p53 in PCa progression through transcriptional and phenotypic analysis.

Main Methods:

• Development of isogenic PCa models expressing R273C-p53 and R273H-p53, with and without wild-type p53.
• Assessment of DNA binding, transcriptional profiles, and canonical tumor suppressor functions.
• In vitro and in vivo phenotypic analysis of heterozygous mutant p53 models.

Main Results:

• Both R273C-p53 and R273H-p53 lost DNA binding and canonical tumor suppressor functions in the absence of wild-type p53.
• In the presence of wild-type p53, both mutants supported p53 target gene expression but displayed distinct cistromic and transcriptional profiles.
• Heterozygous expression of R273C-p53 or R273H-p53 led to distinct in vitro and in vivo phenotypic outcomes.

Conclusions:

• Mutant p53 exerts context-dependent effects, influencing distinct transcriptional profiles and phenotypic outcomes in PCa.
• Mutant p53's role in PCa progression is multifaceted, depending on the specific mutation and the presence of wild-type p53.
• Understanding these context-dependent mechanisms is critical for developing targeted therapies for mutant p53-driven prostate cancer.