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.
Highlights
Breast cancer is the most frequently diagnosed form of cancer among women in the world (GLOBOCAN 2018) [1]; its mortality, has decreased in recent years due to advances in available therapies
The invasive ductal carcinoma (IDC) patients were further divided into the PAM50 subtype, while invasive lobular carcinoma (ILC) and mixed patients mostly exhibit luminal A subtype (90%); there was no subcategorization in their case
We demonstrated the presence of NR2F2 in regulation by ERα in breast cancer cells
Summary
Breast cancer is the most frequently diagnosed form of cancer among women in the world (GLOBOCAN 2018) [1]; its mortality, has decreased in recent years due to advances in available therapies. NR2F2 plays a role in such developmental processes as organogenesis, angiogenesis and lymphogenesis, and at the same time it has been found to have a critical role in tumorigenesis [6] It has been shown in breast cancer that the expression of the NR2F2 is lower in ER-negative cancer and it participates in chemoresistance in cell-type and agent-specific form [7]. Riggs et al reported that a decreased NR2F2 expression correlates with antiestrogen resistance, i.e., if NR2F2 was knocked out of tamoxifen-sensitive MCF-7 cells, the effect of tamoxifen ended, but if NR2F2 was made to overexpress in tamoxifen-resistant cells, sensitivity to tamoxifen was reestablished [8] All this supports that NR2F2 plays an important role in the response given to the treatment of breast cancer patients; the genome-wide regulation of NR2F2 is not known in breast cancer
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