Cathepsins are lysosomal proteases that play an important role in the intracellular degradation of exogenous and endogenous proteins, in activation of enzyme precursors, and in tumor invasion and metastasis. They are normally localized in lysosomes of almost all mammalian cells, but under certain conditions they can be secreted from the cells.
Cathepsin D (CD, EC 3.4.23.5), an aspartyl endopeptidase, is induced by estrogen in certain estrogen receptor (ER)-positive breast cancer cell lines, but is produced constitutively by ER-negative cell lines. Cathepsin D is synthesized as a 52 kDa inactive precursor (pro-cathepsin D). Proteolytic removal of the amino-terminal 43 amino acid fragment and cleavage at an internal site results in an enzymatically active 48 kDa heterodimer consisting of two chains of 14 and 34 kDa.
The level of CD synthesized by cells is increased in response to mitogenic signals from estrogen, EGF, FGF, and IGF- I. The ability of tumor cells to invade the extracellular matrix has been attributed to cathepsins released by tumor cells or associated with the plasma membrane of tumor cells. CD is capable of digesting extracellular matrix proteins in in vivo models. Transfection of the CD gene into rat cells increases their tumorigenicity when injected into nude mice. Indeed, the concentrations of CD are significantly higher in breast carcinomas than in either normal breast tissues or benign breast tumors.
