CD44 regulates cell proliferation, migration, and invasion via modulation of c-Src transcription in human breast cancer cells

Cell Signal. 2015 Sep;27(9):1882-94. doi: 10.1016/j.cellsig.2015.05.002. Epub 2015 May 12.


CD44 was recently identified as a cancer initiation marker on the cell membrane. The cytoplasmic tail of CD44 is known to bind ERM (ezrin, radixin, moesin) proteins, cytoskeletal proteins like ankyrin, and the non-receptor tyrosine kinase c-Src. CD44 transmits its oncogenic signaling via c-Src and its downstream effectors. To investigate the role of CD44 in breast cancer cells, we generated CD44 knock-down cells via retroviral delivery of shRNA against CD44. We found that silencing of CD44 decreased the proliferation, migration, and invasion of breast cancer cells. The expression and activity of cell migration-related proteins, including c-Src, paxillin, and FAK were decreased by CD44 silencing. We also found that the c-Jun protein level was negatively regulated via induction of a GSK-3β-dependent degradation pathway in CD44 knock-down cells. The expression level of Sp1, a target gene product of c-Jun, was also decreased in these cells. Finally, CD44 knock-down suppressed both mRNA and protein levels of c-Src and its downstream MAPK pathway as a result of down-regulation of Sp1 as a transcription factor for c-Src. Collectively, these results indicate that biological changes induced by CD44 silencing are mediated by cumulative down-regulation of c-Jun, Sp1, and c-Src in human breast cancer cells.

Keywords: Breast cancer; CD44; GSK-3β; c-Jun; c-Src.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation*
  • Female
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • MAP Kinase Signaling System*
  • Neoplasm Invasiveness
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Transcription, Genetic*
  • src-Family Kinases / biosynthesis*
  • src-Family Kinases / genetics


  • CD44 protein, human
  • Hyaluronan Receptors
  • Neoplasm Proteins
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human