53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a

被引:44
作者
Li, Xiaoyan [1 ]
Xu, Bing [2 ,3 ]
Moran, Meena S. [4 ]
Zhao, Yuhan [1 ]
Su, Peng [5 ]
Haffty, Bruce G. [6 ]
Shao, Changshun [2 ,3 ]
Yang, Qifeng [1 ,2 ,3 ]
机构
[1] Shandong Univ, Qilu Hosp, Dept Breast Surg, Jinan 250012, Peoples R China
[2] Shandong Univ, Sch Med, Minist Educ, Key Lab Expt Teratol, Jinan 250012, Peoples R China
[3] Shandong Univ, Sch Med, Inst Mol Med & Genet, Jinan 250012, Peoples R China
[4] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA
[5] Shandong Univ, Qilu Hosp, Dept Pathol, Jinan 250012, Peoples R China
[6] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08903 USA
基金
中国国家自然科学基金;
关键词
DNA-DAMAGE; EXPRESSION; CELLS; P53; METASTASIS; ACTIVATION; CHECKPOINT; PROTEINS; PHOSPHORYLATION; MICRORNAS;
D O I
10.1093/carcin/bgs298
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this study, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. Ectopic expression of 53BP1 can significantly inhibit cell proliferation and curb the invasiveness in breast cancer cell lines, whereas knockdown of 53BP1 by RNA interference had the opposite effects. Additionally, 53BP1 markedly inhibited xenograft formation and metastasis of breast cancer cells in nude mice. Both in vitro and in vivo studies revealed that the 53BP1 expression level was inversely correlated to the function of nuclear factor-kappaB (NF-kappa B), which contributes to the invasion and metastasis of breast cancer. Importantly, the inhibitory effect of 53BP1 on NF-kappa B activity was shown to be mediated by the upregulation of miR-146a. Together, our findings demonstrated that 53BP1 has a potent tumor suppressor activity in breast cancer, and it may serve as a novel target for breast cancer prevention and treatment.
引用
收藏
页码:2593 / 2600
页数:8
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