Cathepsin D in breast cancer: mechanisms and clinical applications, a 1999overview

A short review of the literature first confirms the clinical value of cathe psin D as a prognostic marker in breast cancer, when using well standardize d assays. We then summarize results of studies, mostly performed in our lab oratory, aimed at understanding the effect of cathepsin D overexpression on metastasis and the molecular mechanisms involved, Cathepsin D-cDNA transfe ction increases tumor cell proliferation in vitro and the metastatic potent ial of 3Y1-Ad12 embryonic rat tumorigenic cells when injected in vivo into nude mice. The mechanism by which cathepsin D increases the incidence of cl inical metastasis involves increased cell growth and decreased contact inhi bition rather than escape of cancer cells through the basement membrane. Di fferent mechanisms are considered to explain this mitogenic activity. Cathe psin D could act as a protease following its activation at an acidic pH, or as a ligand of different membrane receptors at a more neutral pH. In this case cathepsin D can displace IGFII from the mannose-6-phosphate/ IGFII rec eptor to the IGFI receptor or activate another membrane receptor to be iden tified. The nature of the mechanisms involved in vivo may depend on the mic ro environment of the tumor cells. These studies should guide in the develo pment of new therapies aimed at inhibiting the deleterious effect of overex pressed cathepsin D. (C) 2000 Elsevier Science B.V. All rights reserved.