Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling

Nat Commun. 2015 Apr 15:6:6776. doi: 10.1038/ncomms7776.

Abstract

Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years because of its consistent dysregulation in human epithelial tumours, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumour formation and blunted tumour growth. The abated tumour growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase-deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signalling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Carcinoma / genetics*
  • Carcinoma / metabolism
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Female
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunohistochemistry
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphoproteins
  • Protein Precursors / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-met
  • Serine Endopeptidases / genetics*
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB1 protein, human
  • Gab1 protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Protein Precursors
  • pro-hepatocyte growth factor
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Serine Endopeptidases
  • ST14 protein, human
  • St14 protein, mouse