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

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

doi:10.18632/oncotarget.17532

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.

Highlights

Breast cancer is the most common cancer type in women and poses a major threat to woman’s health
As our first step to explore the role of NR4A1 in cancer, we compared the expression levels of NR4A1 mRNA in human breast cancer and normal breast tissues by analyzing the data sets in the database of Gene Expression Across Normal and Tumor Tissue (GENT) [19]
Analysis of both U133A expression dataset from 2635 breast cancer and 91 normal breast tissue specimens and U133Plus2 expression dataset from 1513 breast cancer and 241 breast normal tissue specimens revealed that NR4A1 expression was significantly downregulated in breast cancers versus normal breast tissues (Figure 1A)

Summary

Introduction

Breast cancer is the most common cancer type in women and poses a major threat to woman’s health. Triplenegative breast cancer (TNBC), which do not express estrogen receptor α (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), accounts for 15% of all breast carcinomas and about 70–80% of basal-like breast cancer [1, 2]. The response of many TNBC patients to chemotherapy is poor [3,4,5]. TNBC that fail to response to initial therapy has a high risk of recurrence and exhibits poor prognosis [1, 4]. There is an urgent need to develop targeted therapies for treating TNBC. Identification and characterization of key molecules that control the growth, progression and metastasis of TNBC cells should facilitate the selection of drug targets and the development of new therapeutic strategies

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