Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment

Research output: Contribution to journalArticle


The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably transfected with human cathepsin D. Cathepsin D extensively cleaved cystatin C in vitro at low pH. Cathepsin D secreted by breast cancer cells also processed cystatin C at the pericellular pH of tumors and so enhancing extracellular proteolytic activity of cysteine cathepsins. Thus, tumor derived cathepsin D assists breast cancer progression by reducing cystatin C activity, which, in turn, enhances cysteine cathepsin proteolytic activity, revealing a new link between protease classes in the protease web.-Laurent-Matha, V., Huesgen, P. F., Masson, O., Derocq, D., Prebois, C., Gary-Bobo, M., Lecaille, F., Rebiere, B., Meurice, G., Orear, C., Hollingsworth, R. E., Abrahamson, M., Lalmanach, G., Overall, C. M., Liaudet-Coopman, E. Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment. FASEB J. 26, 5172-5181 (2012).


  • Valerie Laurent-Matha
  • Pitter F. Huesgen
  • Olivier Masson
  • Danielle Derocq
  • Christine Prebois
  • Magali Gary-Bobo
  • Fabien Lecaille
  • Bertrand Rebiere
  • Guillaume Meurice
  • Cedric Orear
  • Robert E. Hollingsworth
  • Magnus Abrahamson
  • Gilles Lalmanach
  • Christopher M. Overall
  • Emmanuelle Liaudet-Coopman
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology


  • cancer, protease web
Original languageEnglish
Pages (from-to)5172-5181
JournalFASEB Journal
Issue number12
Publication statusPublished - 2012
Publication categoryResearch