Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer.
Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer.
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DOI：
10.18632/oncotarget.17532
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发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Wu H;Bi J;Peng Y;Huo L;Yu X;Yang Z;Zhou Y;Qin L;Xu Y;Liao L;Xie Y;Conneely OM;Jonkers J;Xu J
核受体（NR）超家族包含激素诱导的转录因子，通过调节基因表达来调节许多生理和病理过程。NR 4A 1是一个NR家族成员，目前还没有确定的内源性配体，其在癌症中的作用目前也不清楚，存在争议。在这项研究中，我们的目的是确定NR 4A 1在高度恶性的三阴性乳腺癌（TNBC）中的表达谱和特定作用，这仍然缺乏可用的靶向治疗。生物信息学分析揭示了人TNBC样品中NR 4A 1 mRNA表达的降低。通过免疫组织化学进行的NR 4A 1蛋白表达的半定量分析还鉴定了在小鼠基底样乳腺肿瘤的发展过程中NR 4A 1的进行性减少和在人TNBC样品中NR 4A 1的显著下调。NR 4A 1在TNBC中的表达水平与肿瘤分期、淋巴结转移和疾病复发呈负相关。此外，NR 4A 1在MDA-MB-231（一种几乎没有内源性NR 4A 1的TNBC细胞系）中的异位表达抑制了这些细胞的增殖、活力、迁移和侵袭，并且这些抑制与减弱的JNK 1-AP-1-细胞周期蛋白D1通路相关。NR 4A 1表达也在很大程度上抑制了小鼠中这些细胞源性肿瘤的生长和转移。这些结果表明，NR 4A 1在TNBC中下调，并且NR 4A 1表达的恢复抑制TNBC生长和转移，表明NR 4A 1是TNBC中的肿瘤抑制因子。
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.
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影响因子：
11.2
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
通讯作者：
Safe S
影响因子：
2
作者：
Shin G;Kang TW;Yang S;Baek SJ;Jeong YS;Kim SY
通讯作者：
Kim SY
影响因子：
5.3
作者：
Kolluri, SK;Bruey-Sedano, N;Zhang, XK
通讯作者：
Zhang, XK
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel