FYN promotes mesenchymal phenotypes of basal type breast cancer cells through STAT5/NOTCH2 signaling node

Oncogene. 2018 Apr;37(14):1857-1868. doi: 10.1038/s41388-017-0114-y. Epub 2018 Jan 19.

Abstract

Basal type breast cancer is the most aggressive and has mesenchymal features with a high metastatic ability. However, the signaling node that determines the basal type features in breast cancer remains obscure. Here, we report that FYN among SRC family kinases is required for the maintenance of basal type breast cancer subtype. Importantly, FYN enhanced NOTCH2 activation in basal type breast cancer cells through STAT5-mediated upregulation of Jagged-1 and DLL4 NOTCH ligands, thereby contributed to mesenchymal phenotypes. In addition, we found that high levels of FYN persist in basal type breast cancer cells by a positive feedback loop between FYN and STAT5. FYN interacted directly with STAT5 and increased p-STAT5 that further acts as a transcription factor for FYN. Taken together, our findings demonstrate a pivotal role of FYN and its downstream effectors in maintaining the basal type features in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Phenotype
  • Proto-Oncogene Proteins c-fyn / genetics
  • Proto-Oncogene Proteins c-fyn / physiology*
  • Receptor, Notch2 / physiology*
  • STAT5 Transcription Factor / physiology*
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • NOTCH2 protein, human
  • Receptor, Notch2
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Tumor Suppressor Proteins
  • FYN protein, human
  • Proto-Oncogene Proteins c-fyn