miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer

Mol Cancer Ther. 2014 Dec;13(12):3185-97. doi: 10.1158/1535-7163.MCT-14-0243. Epub 2014 Oct 15.

Abstract

Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer (TNBC). Recent studies have demonstrated that microRNAs (miRNA) play vital roles in the development of TNBC. In this study, we found that miR-185 was strongly downregulated in TNBC tissues and cell lines and that its expression levels were associated with lymph node metastasis, clinical stage, overall survival, and relapse-free survival in TNBC. We also found that ectopic expression of miR-185 inhibited TNBC cell proliferation in vitro and in vivo. We further identified that miR-185 directly targeted DNMT1 and E2F6, which resulted in a marked increase in the expression of BRCA1 at the mRNA and protein levels in TNBC. Our data suggest that miR-185 functions as a tumor suppressor in TNBC development. It is a promising prognostic biomarker and potential therapeutic target for TNBC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / chemistry
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • Down-Regulation
  • E2F6 Transcription Factor / chemistry
  • E2F6 Transcription Factor / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, BRCA1*
  • Humans
  • Lymphatic Metastasis
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • RNA Interference
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology

Substances

  • E2F6 Transcription Factor
  • MIRN185 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human