Aurora B induces epithelial-mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis

Oncogene. 2020 Mar;39(12):2550-2567. doi: 10.1038/s41388-020-1165-z. Epub 2020 Jan 29.

Abstract

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase B / antagonists & inhibitors
  • Aurora Kinase B / metabolism*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal / metabolism*
  • Carcinoma, Ductal / pathology
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial-Mesenchymal Transition*
  • Female
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred NOD
  • Neoplasm Invasiveness
  • Neoplasm Metastasis*
  • Octamer Transcription Factor-3 / metabolism
  • Organophosphates / pharmacology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Stability
  • Quinazolines / pharmacology
  • Signal Transduction
  • Snail Family Transcription Factors / metabolism*
  • Triple Negative Breast Neoplasms / metabolism

Substances

  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • Octamer Transcription Factor-3
  • Organophosphates
  • POU5F1 protein, human
  • Protein Kinase Inhibitors
  • Quinazolines
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • AURKB protein, human
  • Aurora Kinase B
  • Glycogen Synthase Kinase 3 beta