Oncotarget

Research Papers:

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

Hongmei Wu, Jiong Bi, Yan Peng, Lei Huo, Xiaobin Yu, Zhihui Yang, Yunyun Zhou, Li Qin, Yixiang Xu, Lan Liao, Yang Xie, Orla M. Conneely, Jos Jonkers and Jianming Xu _

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Oncotarget. 2017; 8:54364-54377. https://doi.org/10.18632/oncotarget.17532

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Abstract

Hongmei Wu1,7,*, Jiong Bi1,8,*, Yan Peng2,*, Lei Huo3,*, Xiaobin Yu1, Zhihui Yang1,4, Yunyun Zhou5,9, Li Qin1, Yixiang Xu1, Lan Liao1, Yang Xie5, Orla M. Conneely1, Jos Jonkers6 and Jianming Xu1,4

1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA

2Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA

3Department of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA

4Institute for Cancer Medicine, School of Basic Medical Sciences, and Department of Pathology, Xinan Medical University, Luzhou, Sichuan 646000, China

5Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA

6Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, Netherlands

7Current address: College of Life Sciences, Shaanxi Normal University, Xi’an, Shaanxi 710062, China

8Current address: Departments of General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China

9Current address: Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA

*These authors contributed equally to this work

Correspondence to:

Jianming Xu, email: [email protected]

Keywords: triple-negative breast cancer, gene expression, nuclear receptor, NR4A1, tumor suppressor

Received: March 08, 2017     Accepted: April 15, 2017     Published: April 29, 2017

ABSTRACT

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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