BIOLOGICAL AND CLINICAL-SIGNIFICANCE OF CATHEPSIN-D IN BREAST-CANCER METASTASIS

Cathepsin D (cath-D) is an aspartyl lysosomal protease expressed in al l tissues. Most metastatic breast cancer cell lines, unlike normal cel ls, secrete high levels of pro-cath-D. This abnormal secretion is due to both overexpression of the cath-D gene and to an altered processing of the precursor protein. Cath-D gene transcription is increased by e strogen and growth factors in estrogen-receptor-positive breast cancer cells and by an unknown mechanism in estrogen-receptor-negative cells . A large number of independent clinical studies associated high cath- D concentrations in the cytosol of primary breast cancers with increas ed risk of subsequent metastasis. The amino acid sequence of cath-D an alyzed in two breast cancer cell lines is normal, but glycosylation ap pears to be different with more acidic isoforms. To assess the potenti al role of this protease in cancer metastasis, we transfected a human cDNA cath-D expression vector in 3Y1-Ad12 embryonic rat tumorigenic ce lls which did not secrete the proenzyme. A moderate overexpression of human cath-D was sufficient to increase the metastatic potential of th ese cells in nude mice. Tile mechanism of cath-D-induced metastasis se ems to require maturation of the proenzyme, in endosomes and in large acidic compartments identified as phagosomes. Rather than increase can cer cell escape from the primary tumor through basement membrane degra dation as proposed for neutral proteinases, cath-D appears to facilita te cell growth at distant sites. The mechanism of this indirect mitoge nic effect is discussed from results obtained in different models. Dif ferent cath-D substrates (growth inhibitors, precursors of growth fact ors, etc.) are proposed to mediate this activity.