Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression

Abstract

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.

Astragaloside IV Induced miR-134 Expression Reduces EMT and Increases Chemotherapeutic Sensitivity by Suppressing CREB1 Signaling in Colorectal Cancer Cell Line SW-480

“…Qu et al showed that miR-150 significantly enhanced EMT signaling by regulating the CREB1 expression in CRC cells [36]. He et al demonstrated that miR-27b-3p directly targeted and inhibited the expression of CREB1, which played a key role in the resistance to tamoxifen in breast cancer cells [37]. Our results showed that down-regulation of CREB1 inhibited cell migration, invasion and induced cell apoptosis.…”

Long noncoding RNA DQ786243 interacts with miR‐506 and promotes progression of ovarian cancer through targeting cAMP responsive element binding protein 1

“…20,21,27,28 Therefore, we further investigated whether miR-506 could directly regulate CREB1 in ovarian cancer. 20,21,27,28 Therefore, we further investigated whether miR-506 could directly regulate CREB1 in ovarian cancer.…”

miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22

“…MiR-148a and miR-152 were able to reduce tamoxifen resistance in ER-positive breast cancer via downregulating ALCAM [10]. Downregulation of microRNA-27b-3p enhanced tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression [8]. Therefore, miRNAs may be a novel therapeutic approach to sensitizing and suppressing the growth of tamoxifen-resistant breast tumors.…”

“…Recent studies have reported that abnormal expression of miRNAs plays an important role in tamoxifen resistance [2,[7][8][9][10]. MiRNAs belong to a novel class of regulatory determinants which are small non-coding RNAs, about 20-23 nucleotides in length.…”