Huo Yanying, Selenica Pier, Mahdi Amar H, Pareja Fresia, Kyker-Snowman Kelly, Chen Ying, Kumar Rahul, Da Cruz Paula Arnaud, Basili Thais, Brown David N, Pei Xin, Riaz Nadeem, Tan Yongmei, Huang Yu-Xiu, Li Tao, Barnard Nicola J, Reis-Filho Jorge S, Weigelt Britta, Xia Bing
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
NPJ Breast Cancer. 2021 Apr 23;7(1):45. doi: 10.1038/s41523-021-00253-5.
Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.
BRCA1、BRCA2和PALB2的遗传性突变会导致患乳腺癌的高风险。在此，我们在未生育雌性小鼠的乳腺中分别单独或联合对Brca1、Palb2和Brca2进行平行条件性敲除（CKO），同时保留一份Trp53。我们观察到这三个基因在其基本肿瘤抑制活性方面具有功能等效性，Palb2和Brca2存在线性上位效应，但Brca1和Palb2在乳腺肿瘤抑制中具有互补作用，因为Palb2或Brca2与Brca1联合缺失会导致肿瘤形成延迟。全外显子测序（WES）揭示了Brca1与Palb2或Brca2缺失肿瘤之间的异同。对小鼠乳腺和培养的人类细胞的分析表明，BRCA1和PALB2的联合缺失导致高水平的活性氧（ROS）并增加细胞凋亡，这表明氧化应激与Brca1;Palb2双CKO小鼠的肿瘤发生延迟有关。BRCA1与PALB2/BRCA2之间的功能互补性以及ROS在肿瘤发生中的作用需要进一步研究。
