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

Cell Death Dis. 2016 Nov 3;7(11):e2454. doi: 10.1038/cddis.2016.361.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Survival / drug effects
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Down-Regulation / drug effects*
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Biological
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tamoxifen / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Estrogens
  • MIRN27 microRNA, human
  • MicroRNAs
  • NR5A2 protein, human
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Tamoxifen