Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

Oncol Rep. 2015 Sep;34(3):1345-52. doi: 10.3892/or.2015.4103. Epub 2015 Jul 2.


Fibronectin (FN) has been recognized as the key element in promoting cell adhesion, migration and oncogenic transformation. αvβ6 integrin binds with FN in an RGD-dependent manner and is associated with invasion and poor prognosis in many types of cancers. The extracellular matrix (ECM) is commonly degraded and becomes disorganized in cancers. Previous studies have shown that FN can be degraded into fragments by MMP-9 in vitro; MMP-9 expression is upregulated in breast cancer, therefore, the role of degraded FN in breast cancer progression needs to be investigated. In the present study, expression of β6 integrin in breast cancer tissues was analyzed. The data were quite consistent with the hypothesis that β6 integrin expression is an indicator of poor prognosis. Cell surface expression of β6 integrin was correlated with the invasive behavior of the breast cancer cell lines. MMP-9-degraded FN was used to explore its effects on cell invasion and expression of β6 integrin. The results indicated that MMP-9-degraded FN can adjust constituents of the αvβ6 heterodimers at the early phase and significantly elevate amounts of β6 integrin subunits at a later period. To better elucidate the mechanism by which β6 integrin regulates FN-induced cell migration and invasion, we determined the expression and activity of the downstream kinases of β6 integrin, and elucidated that focal adhesion kinase (FAK)-Src interaction promoted the invasion and migration of breast cancer cells after treatment of MMP-9-degraded FN through the Erk1/2 and PI3K/Akt/Smad‑1/5/8 pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Movement / genetics*
  • Female
  • Fibronectins / genetics*
  • Fibronectins / metabolism
  • Focal Adhesion Kinase 1 / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrin beta Chains / genetics*
  • Integrin beta Chains / metabolism
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System / genetics
  • MCF-7 Cells
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • Neoplasm Invasiveness / genetics*
  • Oncogene Protein v-akt / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Proteolysis
  • Smad Proteins / genetics
  • src-Family Kinases / genetics


  • Fibronectins
  • Integrin beta Chains
  • Smad Proteins
  • integrin beta6
  • Phosphatidylinositol 3-Kinases
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • src-Family Kinases
  • Oncogene Protein v-akt
  • Matrix Metalloproteinase 9