Embryology Laboratory, Department of Anatomy, College of Medicine, Yonsei University, Seoul 03722, Korea.
Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Korea.
Cells. 2021 Jun 29;10(7):1633. doi: 10.3390/cells10071633.
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.
内分泌治疗用于治疗雌激素受体 (ER) 阳性乳腺癌。他莫昔芬对这种癌症亚型有效。尽管如此，大约 30%接受他莫昔芬治疗的患者会产生耐药性，从而带来治疗挑战。NR4A1 在与致癌、凋亡、DNA 修复、增殖和炎症相关的过程中发挥关键作用。然而，NR4A1 在他莫昔芬耐药的 ER 阳性乳腺癌中的作用尚未阐明。在这里，我们提出 NR4A1 是克服他莫昔芬耐药性的有前途的靶点。与 MCF7 细胞相比，他莫昔芬耐药 MCF7（TamR）细胞中的 NR4A1 基因表达下调。Kaplan-Meier 图用于鉴定高 NR4A1 表达与接受他莫昔芬治疗的 ER 阳性乳腺癌患者的生存率提高相关。获得和丧失功能实验表明，NR4A1 通过调节细胞增殖、迁移、侵袭和凋亡来恢复对他莫昔芬的敏感性。NR4A1 定位于细胞质中增强了凋亡因子的表达。计算机模拟和体外分析表明，NR4A1 通过抑制 ERK 信号通路增强 ER 阳性乳腺癌对他莫昔芬的反应性，表明 NR4A1/ERK 信号轴调节他莫昔芬耐药性。这些结果表明，NR4A1 可能是克服 ER 阳性乳腺癌他莫昔芬耐药性的潜在治疗靶点。
