NR2F2 Orphan Nuclear Receptor is Involved in Estrogen Receptor Alpha-Mediated Transcriptional Regulation in Luminal A Breast Cancer Cells

Abstract

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 NR2F2 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.

Molecular Mechanisms of Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer

“…The antiproliferative effects of tamoxifen are enhanced by COUP-TFII overexpression ( 68 ). Similar to other corepressors, the expression of NR2F2 is also decreased in tamoxifen resistance ( 73 ).…”

NR2F2 Regulates Cell Proliferation and Immunomodulation in Whartons’ Jelly Stem Cells

“…Previous studies have shown that NR2F2 expression was positively correlated with cell invasion, migration, and the expression of N-cadherin and vimentin [ 33 ] and has a key role in ERα-mediated transcription [ 34 ]. NR2F2 can also promote tumor cell proliferation, epithelial-mesenchymal transition, and invasive characteristics and inhibit tumor differentiation and immune cell infiltration by regulating transcriptional programs commonly found in mouse and human squamous cell carcinomas [ 35 ].…”

Abnormal hsa_circ_0003948 expression affects chronic periodontitis development by regulating miR‐144‐3p/NR2F2/PTEN signaling

“…Further studies have validated the fact that miR‐144‐3p expression suppresses NR2F2 expression. NR2F2 is a steroid/thyroid hormone receptor with a crucial function in angiogenesis, organogenesis, cardiovascular development, and tumorigenesis 18,19 . NR2F2 upregulation accelerates cell proliferation 20 .…”