Snail1 induced in breast cancer cells in 3D collagen I gel environment suppresses cortactin and impairs effective invadopodia formation

Biochim Biophys Acta. 2014 Sep;1843(9):2037-54. doi: 10.1016/j.bbamcr.2014.05.007. Epub 2014 May 24.


Although an in vitro 3D environment cannot completely mimic the in vivo tumor site, embedding tumor cells in a 3D extracellular matrix (ECM) allows for the study of cancer cell behaviors and the screening of anti-metastatic reagents with a more in vivo-like context. Here we explored the behaviors of MDA-MB-231 breast cancer cells embedded in 3D collagen I. Diverse tumor environmental conditions (including cell density, extracellular acidity, or hypoxia as mimics for a continuous tumor growth) reduced JNKs, enhanced TGFβ1/Smad signaling activity, induced Snail1, and reduced cortactin expression. The reduced JNKs activity blocked efficient formation of invadopodia labeled with actin, cortactin, or MT1-MMP. JNKs inactivation activated Smad2 and Smad4, which were required for Snail1 expression. Snail1 then repressed cortactin expression, causing reduced invadopodia formation and prominent localization of MT1-MMP at perinuclear regions. MDA-MB-231 cells thus exhibited less efficient collagen I degradation and invasion in 3D collagen I upon JNKs inhibition. These observations support a signaling network among JNKs, Smads, Snail1, and cortactin to regulate the invasion of MDA-MB-231 cells embedded in 3D collagen I, which may be targeted during screening of anti-invasion reagents.

Keywords: 3D collagen; Cortactin; Invasion; JNK; Snail1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cattle
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement
  • Cell Nucleus / metabolism
  • Collagen Type I / pharmacology*
  • Cortactin / genetics
  • Cortactin / metabolism*
  • Female
  • Gels
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Matrix Metalloproteinase 14 / metabolism
  • Neoplasm Invasiveness
  • Phosphoserine / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-jun / metabolism
  • Pseudopodia / drug effects
  • Pseudopodia / metabolism*
  • Signal Transduction
  • Smad Proteins / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Microenvironment / drug effects*


  • Actins
  • CTTN protein, human
  • Collagen Type I
  • Cortactin
  • Gels
  • Proto-Oncogene Proteins c-jun
  • SNAI1 protein, human
  • Smad Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Phosphoserine
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 14