Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2308807120. doi: 10.1073/pnas.2308807120. Epub 2023 Aug 14.
The tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent 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 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.
抑癌基因在大多数三阴性乳腺癌（TNBC）患者中早期发生突变。最常见的改变是导致肿瘤侵袭性的错义突变。我们开发了一种自发的体细胞 K14-Cre 驱动的 TNBC 小鼠模型，该模型具有 p53R172H 和 p53R245W 突变，其中突变型 p53 可以在遗传上打开和关闭，而肿瘤微环境保持完整且野生型 p53。这些小鼠在 1 年内发展为 TNBC。在这些肿瘤中体内删除突变型 p53R172H 或 p53R245W 会削弱其肿瘤生长并显著延长小鼠的存活时间。下游分析表明，删除突变型激活了环状 GMP-AMP 合酶-干扰素基因刺激物途径，但不会引起细胞凋亡，提示存在其他肿瘤消退机制。此外，我们确定只有具有稳定突变型 p53 的肿瘤才依赖突变型 p53 生长。
