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

12 Citations (Scopus)

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 - 2017

Fingerprint

Nuclear Receptor Subfamily 4, Group A, Member 1
Triple Negative Breast Neoplasms
Neoplasms
Neoplasm Metastasis
Down-Regulation
Cell Migration Inhibition
Physiological Phenomena
Cyclin D1
Transcription Factor AP-1
Pathologic Processes
Cytoplasmic and Nuclear Receptors
Growth
Computational Biology
Nuclear Family
Transcription Factors
Lymph Nodes
Immunohistochemistry
Hormones
Breast Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. / Wu, Hongmei; Bi, Jiong; Peng, Yan; Huo, Lei; Yu, Xiaobin; Yang, Zhihui; Zhou, Yunyun; Qin, Li; Xu, Yixiang; Liao, Lan; Xie, Yang; Conneely, Orla M.; Jonkers, Jos; Xu, Jianming.

In: Oncotarget, Vol. 8, No. 33, 2017, p. 54364-54377.

Research output: Contribution to journalArticle

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 2017, 'Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer', Oncotarget, vol. 8, no. 33, pp. 54364-54377. https://doi.org/10.18632/oncotarget.17532
Wu, Hongmei ; Bi, Jiong ; Peng, Yan ; Huo, Lei ; Yu, Xiaobin ; Yang, Zhihui ; Zhou, Yunyun ; Qin, Li ; Xu, Yixiang ; Liao, Lan ; Xie, Yang ; Conneely, Orla M. ; Jonkers, Jos ; Xu, Jianming. / Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. In: Oncotarget. 2017 ; Vol. 8, No. 33. pp. 54364-54377.
@article{86d2a9a5a5494f848fc26afaabe6168a,
title = "Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer",
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.",
keywords = "Gene expression, NR4A1, Nuclear receptor, Triple-negative breast cancer, Tumor suppressor",
author = "Hongmei Wu and Jiong Bi and Yan Peng and Lei Huo and Xiaobin Yu and Zhihui Yang and Yunyun Zhou and Li Qin and Yixiang Xu and Lan Liao and Yang Xie and Conneely, {Orla M.} and Jos Jonkers and Jianming Xu",
year = "2017",
doi = "10.18632/oncotarget.17532",
language = "English (US)",
volume = "8",
pages = "54364--54377",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "33",

}

TY - JOUR

T1 - Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer

AU - Wu, Hongmei

AU - Bi, Jiong

AU - Peng, Yan

AU - Huo, Lei

AU - Yu, Xiaobin

AU - Yang, Zhihui

AU - Zhou, Yunyun

AU - Qin, Li

AU - Xu, Yixiang

AU - Liao, Lan

AU - Xie, Yang

AU - Conneely, Orla M.

AU - Jonkers, Jos

AU - Xu, Jianming

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Gene expression

KW - NR4A1

KW - Nuclear receptor

KW - Triple-negative breast cancer

KW - Tumor suppressor

UR - http://www.scopus.com/inward/record.url?scp=85026657035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026657035&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.17532

DO - 10.18632/oncotarget.17532

M3 - Article

VL - 8

SP - 54364

EP - 54377

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 33

ER -