NR2F2 Orphan Nuclear Receptor is Involved in Estrogen Receptor Alpha-Mediated Transcriptional Regulation in Luminal A Breast Cancer Cells.
Erdős Edina,Bálint Bálint László
International journal of molecular sciences
Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) is a member of the steroid/thyroid hormone receptor superfamily with a crucial role in organogenesis, angiogenesis, cardiovascular development and tumorigenesis. However, there is limited knowledge about the cistrome and transcriptome of NR2F2 in breast cancer. In this study, we mapped the regulatory mechanism by NR2F2 using functional genomic methods. To investigate the clinical significance of NR2F2 in breast cancer, The Cancer Genome Atlas (TCGA) data were used. These results show that a high is associated with better survival of a specific subset of patients, namely those with luminal A breast cancer. Therefore, genome-wide NR2F2 and estrogen receptor alpha (ERα) binding sites were mapped in luminal A breast cancer cells using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq), revealing that most NR2F2 overlap with ERα that are co-occupied by forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA3) in active enhancer regions. NR2F2 overlaps with highly frequent ERα chromatin interactions, which are essential for the formation of ERα-bound super-enhancers. In the process of the transcriptome profiling of NR2F2-depleted breast cancer cells such differentially expressed genes have been identified that are involved in endocrine therapy resistance and are also ERα target genes. Overall, these findings demonstrate that the NR2F2 nuclear receptor has a key role in ERα-mediated transcription and it can offer a potential therapeutic target in patients with luminal A breast cancer.
NR2F2 plays a major role in insulin-induced epithelial-mesenchymal transition in breast cancer cells.
Xia Baili,Hou Lijun,Kang Huan,Chang Wenhui,Liu Yi,Zhang Yanli,Ding Yi
BACKGROUND:The failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role. Hyperinsulinemia, the hallmark of Type 2 diabetes mellitus (T2DM), has been regarded as a key risk factor for the progression of breast cancer. Nuclear receptor subfamily 2, group F, member 2 (NR2F2) has been implicated in the development of breast cancer, however its contribution to insulin-induced EMT in breast cancer remains unclear. METHODS:Overexpression and knockdown of NR2F2 were used in two breast cancer cell lines, MCF-7 and MDA-MB-231 to investigate potential mechanisms by which NR2F2 leads to insulin-mediated EMT. To elucidate the effects of insulin and signaling events following NR2F2 overexpression and knockdown, Cells' invasion and migration capacity and changes of NR2F2, E-cadherin, N-cadherin and vimentin were investigated by real-time RT-PCR and western blot. RESULTS:Insulin stimulation of these cells increased NR2F2 expression levels and promoted cell invasion and migration accompanied by alterations in EMT-related molecular markers. Overexpression of NR2F2 and NR2F2 knockdown demonstrated that NR2F2 expression was positively correlated with cell invasion, migration and the expression of N-cadherin and vimentin. In contrast, NR2F2 had an inverse correlation with E-cadherin expression. In MDA-MB-231, both insulin-induced cell invasion and migration and EMT-related marker alteration were abolished by NR2F2 knockdown. CONCLUSIONS:These results suggest that NR2F2 plays a critical role in insulin-mediated breast cancer cell invasion, migration through its effect on EMT.