Abstract
Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
Highlights
Our results showed that the mRNA and protein levels of NR4A1 were significantly downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to those in
Gene Set Enrichment Analysis (GSEA) conducted between the NR4A1 high and low groups revealed that high mRNA levels of NR4A1 are correlated with the negative regulation of mitogen-activated protein kinase (MAPK) cascade (Figure S6A,B)
We demonstrated that NR4A1, whose expression was downregulated in TamR
Summary
Breast cancer is one of the most common cancers in women worldwide [1], and it can be classified into four molecular subtypes based on gene expression profiling [2]. Among these subtypes, estrogen receptor (ER)-positive breast cancer accounts for approximately. Tamoxifen, which is the most widely used endocrine therapy, has significant therapeutic effects; approximately one-third of patients with ER-positive breast cancer treated with tamoxifen for 5 years acquire resistance to the drug, which reduces its therapeutic effect and shortens the survival of patients [4,5,6]
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