Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression.
Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression.
复制标题
microRNA-27b-3p 的下调通过增加 NR5A2 和 CREB1 的表达来增强乳腺癌中他莫昔芬的耐药性。
DOI：
10.1038/cddis.2016.361
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发表时间：
2016-11-03
影响因子：
9
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Zhu J;Zou Z;Nie P;Kou X;Wu B;Wang S;Song Z;He J
雌激素依赖性乳腺癌通常使用芳香酶抑制剂或雌激素受体（ER）拮抗剂进行治疗。三苯氧胺作为一种主要的雌激素受体拮抗剂，常用于治疗ERα阳性的乳腺癌患者。然而，大多数ERα阳性患者对他莫昔芬无应答，原因是存在内在或获得性耐药。据报道，microRNA（miRNAs）的表达和功能改变与他莫昔芬耐药性相关。在这项研究中，我们研究了miR-27 b-3 p在乳腺癌对他莫昔芬耐药中的作用。miR-27 b-3 p水平在他莫昔芬耐药乳腺癌细胞中与其亲本细胞相比显著降低。此外，miR-27 b-3 p在乳腺肿瘤组织中相对于邻近非肿瘤组织也显著下调。此外，miR-27 b-3 p在他莫昔芬耐药患者的乳腺癌组织中的表达水平低于未接受他莫昔芬治疗的患者。值得注意的是，在乳腺癌细胞中，他莫昔芬抑制miR-27 b-3 p表达，而雌激素诱导miR-27 b-3 p表达。此外，我们还在体内外模型中提供了miR-27 b-3 p增强乳腺癌细胞对他莫昔芬敏感性的实验证据。更重要的是，我们验证了miR-27 b-3 p直接靶向并抑制核受体亚家族5 A组成员2（NR 5A 2）和cAMP反应元件结合蛋白1（CREB 1）的表达，因此增强了他莫昔芬诱导的乳腺癌细胞毒性。最后，发现乳腺癌组织中miR-27 b-3 p水平与NR 5A 2和CREB 1水平均显著负相关。我们的研究结果提供了进一步的证据，miR-27 b-3 p可能被认为是一个新的和潜在的目标，用于诊断和治疗他莫昔芬耐药的乳腺癌。
Estrogen-dependent breast cancer is often treated with the aromatase inhibitors or estrogen receptor (ER) antagonists. Tamoxifen as a major ER antagonist is usually used to treat those patients with ERα-positive breast cancer. However, a majority of patients with ERα positive fail to respond to tamoxifen due to the presence of intrinsic or acquired resistance to the drug. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. In this study, we investigated the role of miR-27b-3p in resistance of breast cancer to tamoxifen. MiR-27b-3p levels were remarkably reduced in the tamoxifen-resistant breast cancer cells compared with their parental cells. In addition, miR-27b-3p was also significantly downregulated in breast tumor tissues relative to adjacent non-tumor tissues. Moreover, the expression levels of miR-27b-3p were lower in the breast cancer tissues from tamoxifen-resistant patients compared with that from untreated-tamoxifen patients. Notably, tamoxifen repressed miR-27b-3p expression, whereas estrogen induced miR-27b-3p expression in breast cancer cells. Besides, we provided experimental evidences that miR-27b-3p enhances the sensitivity of breast cancer cells to tamoxifen in vitro and in vivo models. More importantly, we validated that miR-27b-3p directly targeted and inhibited the expression of nuclear receptor subfamily 5 group A member 2 (NR5A2) and cAMP-response element binding protein 1 (CREB1) and therefore augmented tamoxifen-induced cytotoxicity in breast cancer. Lastly, miR-27b-3p levels were found to be significantly negatively correlated with both NR5A2 and CREB1 levels in breast cancer tissues. Our findings provided further evidence that miR-27b-3p might be considered as a novel and potential target for the diagnosis and treatment of tamoxifen-resistant breast cancer.