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, Jianming Xu

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)54364-54377
Number of pages14
JournalOncotarget
Volume8
Issue number33
DOIs
StatePublished - Jan 1 2017

Keywords

  • Gene expression
  • NR4A1
  • Nuclear receptor
  • Triple-negative breast cancer
  • Tumor suppressor

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Wu, H., Bi, J., Peng, Y., Huo, L., Yu, X., Yang, Z., Zhou, Y., Qin, L., Xu, Y., Liao, L., Xie, Y., Conneely, O. M., Jonkers, J., & Xu, J. (2017). Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. Oncotarget, 8(33), 54364-54377. https://doi.org/10.18632/oncotarget.17532