The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer

Int J Mol Sci. 2015 Jan 30;16(2):3148-62. doi: 10.3390/ijms16023148.


Upregulation of miR-21 (microRNA-21) and downregulation of miR-34b/c have been found in breast cancer (BC). However, their regulation mechanism and function roles in BC have not been fully addressed. Here, we report that miR-21 levels were inversely correlated with miR-34b/c levels in BC. MiR-21 upregulation contributes to PTEN downregulation, which is beneficial for the activation of PI3K/AKT signaling. The activation of AKT phosphorylates FOXO3a, triggering relocalization of FOXO3a proteins from the nucleus to the cytoplasm. FOXO3a is a newly identified transcription factor responsible for miR-34b/c expression. Downregulation of nuclear FOXO3a decreased the expression levels of miR-34b and miR-34c in breast cancer cells, in which p53 was mutated. We also found upregulation of circulating miR-21 and downregulation of circulating miR-34b/c in BC patients' serum. More importantly, we showed that systemic delivery of miR-34b/c or with anti-miR-21 significantly inhibited breast tumor growth in vivo. These results suggest that high circulating levels of miR-21 and low levels of miR-34b/c may provide potential biomarkers for BC diagnosis, and systemic delivery of miR-34b/c has potential as a therapeutic option for BC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Down-Regulation
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / blood
  • MicroRNAs / metabolism*
  • MicroRNAs / pharmacology
  • PTEN Phosphohydrolase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • Biomarkers
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • MIRN21 microRNA, human
  • MIRN34 microRNA, human
  • MicroRNAs
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human