The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brca1, Brca2 and Palb2 conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds. Rather than mammary tumors, Palb2 and Trp53 compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline Trp53 inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.

BRCA1-PALB2-BRCA2 轴或 BRCA 通路在维持基因组稳定性和抑制乳腺癌和其他几种癌症中起关键作用。由于来自 Brca1、Brca2 和 Palb2 条件性敲除模型的人 BRCA1 乳腺癌和小鼠乳腺肿瘤中的频繁 p53 突变，通常认为p53失活加速了BRCA1/2 和 PALB2 相关的肿瘤发生。在这里，我们研究了具有Palb2突变的小鼠的肿瘤发展，该突变在不同Trp53背景中脱离了 PALB2-BRCA1 相互作用。而不是乳腺肿瘤，Palb2和Trp53复合突变小鼠发育，潜伏期大大降低，淋巴瘤和肉瘤通常与种系Trp53失活有关。全外显子组测序未能发现相同肿瘤类型的Trp53单突变体和Palb2;Trp53复合突变小鼠之间基因组特征的任何显着差异。这些结果表明，BRCA 通路的缺失加速了 p53 相关肿瘤的发展，可能不会改变基本的致瘤过程。