Triple-Negative Breast Tumors Are Dependent on Mutant p53 for Growth and Survival

Authors

Denada Dibra
Sydney M Moyer
Adel K El-Naggar
Yuan Qi
Xiaoping Su
Guillermina Lozano

Publication Date

8-22-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2308807120

PMID

37579145

PMCID

PMC10450424

PubMedCentral® Posted Date

8-14-2023

PubMedCentral® Full Text Version

Post-print

Abstract

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.

Keywords

Animals, Humans, Mice, Genes, p53, Mutation, Mutation, Missense, Triple Negative Breast Neoplasms, Tumor Microenvironment, Tumor Suppressor Protein p53, mouse models, mutant p53 stability, tumor cell vulnerabilities, breast cancer

Published Open-Access

yes

Recommended Citation

Dibra, Denada; Moyer, Sydney M; El-Naggar, Adel K; et al., "Triple-Negative Breast Tumors Are Dependent on Mutant p53 for Growth and Survival" (2023). Faculty, Staff and Student Publications. 4786.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4786