Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer

被引:38
作者
Wu, Hongmei [1 ,8 ]
Bi, Jiong [1 ,9 ]
Peng, Yan [2 ]
Huo, Lei [3 ]
Yu, Xiaobin [1 ]
Yang, Zhihui [1 ,4 ,5 ]
Zhou, Yunyun [6 ,10 ]
Qin, Li [1 ]
Xu, Yixiang [1 ]
Liao, Lan [1 ]
Xie, Yang [6 ]
Conneely, Orla M. [1 ]
Jonkers, Jos [7 ]
Xu, Jianming [1 ,4 ,5 ]
机构
[1] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[2] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX 75390 USA
[3] UT MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[4] Xinan Med Univ, Inst Canc Med, Sch Basic Med Sci, Luzhou 646000, Sichuan, Peoples R China
[5] Xinan Med Univ, Dept Pathol, Luzhou 646000, Sichuan, Peoples R China
[6] UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA
[7] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands
[8] Shaanxi Normal Univ, Coll Life Sci, Xian 710062, Shaanxi, Peoples R China
[9] Sun Yat Sen Univ, Dept Gen Surg Lab, Affiliated Hosp 1, Guangzhou 510080, Guangdong, Peoples R China
[10] Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA
基金
美国国家卫生研究院;
关键词
triple-negative breast cancer; gene expression; nuclear receptor; NR4A1; tumor suppressor; CYCLIN D1 EXPRESSION; ORPHAN-RECEPTOR; APOPTOSIS; CELLS; METASTASIS; PROSTATE; GROWTH; ALPHA; NUR77; TR3;
D O I
10.18632/oncotarget.17532
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The nuclear receptor (NR) superfamily contains hormone-inducible transcription factors that regulate many physiological and pathological processes through regulating gene expression. NR4A1 is an NR family member that still does not have an identified endogenous ligand, and its role in cancer is also currently unclear and controversial. In this study, we aimed to define the expression profiles and specific role of NR4A1 in the highly malignant triple-negative breast cancer (TNBC), which still lacks available targeted therapies. Bioinformatic analysis revealed a decrease of NR4A1 mRNA expression in human TNBC samples. Semi-quantitative analysis of NR4A1 protein expression by immunohistochemistry also identified a progressive NR4A1 reduction during the development of mouse basal-like mammary tumors and a significant NR4A1 downregulation in human TNBC samples. Furthermore, the expression levels of NR4A1 in human TNBC were negatively associated with tumor stage, lymph node metastasis and disease recurrence. Moreover, ectopic expression of NR4A1 in MDA-MB-231, a TNBC cell line with little endogenous NR4A1, inhibited the proliferation, viability, migration and invasion of these cells, and these inhibitions were associated with an attenuated JNK1-AP-1-cyclin D1 pathway. NR4A1 expression also largely suppressed the growth and metastasis of these cell-derived tumors in mice. These results demonstrate that NR4A1 is downregulated in TNBC and restoration of NR4A1 expression inhibits TNBC growth and metastasis, suggesting that NR4A1 is a tumor suppressor in TNBC.
引用
收藏
页码:54364 / 54377
页数:14
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