NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer
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 associat...
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MDPI AG
2021-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/7/1633 |
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| author | Yu Cheon Kim Clara Yuri Kim Ji Hoon Oh Myoung Hee Kim |
| author_facet | Yu Cheon Kim Clara Yuri Kim Ji Hoon Oh Myoung Hee Kim |
| author_sort | Yu Cheon Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:57:59Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T09:57:59Z |
| publishDate | 2021-06-01 |
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| spelling | doaj.art-a73dc23cdf8545cf8d8e554295dd7a852023-11-22T02:14:19ZengMDPI AGCells2073-44092021-06-01107163310.3390/cells10071633NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast CancerYu Cheon Kim0Clara Yuri Kim1Ji Hoon Oh2Myoung Hee Kim3Embryology Laboratory, Department of Anatomy, College of Medicine, Yonsei University, Seoul 03722, KoreaEmbryology Laboratory, Department of Anatomy, College of Medicine, Yonsei University, Seoul 03722, KoreaEmbryology Laboratory, Department of Anatomy, College of Medicine, Yonsei University, Seoul 03722, KoreaEmbryology Laboratory, Department of Anatomy, College of Medicine, Yonsei University, Seoul 03722, KoreaEndocrine 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.https://www.mdpi.com/2073-4409/10/7/1633NR4A1ERK signaling pathwaytamoxifen resistancebreast cancer |
| spellingShingle | Yu Cheon Kim Clara Yuri Kim Ji Hoon Oh Myoung Hee Kim NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer Cells NR4A1 ERK signaling pathway tamoxifen resistance breast cancer |
| title | NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer |
| title_full | NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer |
| title_fullStr | NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer |
| title_full_unstemmed | NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer |
| title_short | NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer |
| title_sort | nr4a1 regulates tamoxifen resistance by suppressing erk signaling in er positive breast cancer |
| topic | NR4A1 ERK signaling pathway tamoxifen resistance breast cancer |
| url | https://www.mdpi.com/2073-4409/10/7/1633 |
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