突变体
生物
癌症研究
三阴性乳腺癌
错义突变
抑癌基因
体细胞
基因
乳腺癌
突变
分子生物学
癌症
癌变
遗传学
作者
Denada Dibra,Sydney M. Moyer,Adel K. El‐Naggar,Yuan Qi,Xiaoping Su,Guillermina Lozano
标识
DOI:10.1073/pnas.2308807120
摘要
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.
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