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Updated: Jul 19, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Triple-negative breast tumors are dependent on mutant p53 for growth and survival
Denada Dibra1, Sydney M Moyer1,2, Adel K El-Naggar3
1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
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.
Insights
Targeting mutant TP53 in triple-negative breast cancer (TNBC) slows tumor growth. Genetic deletion of mutant TP53 activates immune pathways and extends survival, revealing a dependency in aggressive TNBC tumors.
Area of Science:
- Oncology
- Cancer Genetics
- Tumor Suppressor Genes
Background:
- The TP53 tumor suppressor gene is frequently mutated in triple-negative breast cancer (TNBC), contributing to tumor aggressiveness.
- Missense mutations in TP53 are the most common alterations observed in TNBC patients.
Purpose of the Study:
- To develop and utilize a genetically engineered mouse model to investigate the role of mutant TP53 in TNBC.
- To assess the therapeutic potential of genetically ablating mutant TP53 in established TNBC tumors.
Main Methods:
- Development of an autochthonous K14-Cre driven TNBC mouse model harboring switchable p53R172H and p53R245W mutations.
- Genetic deletion of mutant p53 in established tumors to evaluate its impact on tumor growth and survival.
- Downstream molecular analyses to elucidate mechanisms of tumor regression following mutant p53 deletion.
Main Results:
- The developed TNBC mouse model exhibited a median latency of 1 year.
- In vivo deletion of mutant p53R172H or p53R245W significantly blunted tumor growth and extended mouse survival.
- Mutant TP53 deletion activated the cGAS-STING pathway but did not induce apoptosis, suggesting alternative tumor regression mechanisms.
Conclusions:
- Mutant TP53 is crucial for the growth of a subset of TNBCs, and its genetic deletion can lead to tumor regression.
- The findings highlight the potential of targeting mutant TP53 as a therapeutic strategy for TNBC.
- Activation of the cGAS-STING pathway is implicated in the regression of TNBC tumors upon mutant TP53 ablation.
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