Oestrogen-induced pro-cathepsin D in breast cancer: from biology to clinical applications

In addition to secreted growth factors, acting as autocrine or paracrine mitogens, breast cancer cellssecrete other proteins whose function and significance in mammary carcinogenesis may be important. Among them, proteases are particularly interesting since it has been suggested that they play a role in metastatic process, and since at least two of them, the tissue type plasminogen activator and pro- cathepsin D, the precursor of a lysosomal protease, are induced by oestrogens and secreted in excess in some mammary cancer cells. In oestrogen-receptor-positive human breast cancer celllines (MCF7, ZR75–1), oestrogens stimulate cell proliferation and specifically increase the secretion into the culture medium of a 52,000-dalton (52-kDa) glycoprotein identified as the secreted precursor of a cathepsin Dbearing mannose-6-phosphatesignals, which is routed to lysosomes via mannose-6-phosphate-IGF-II receptors. We have determined the structure of this procathepsin D by sequencing its complete cDNA sequence, its chromosomal localisation and its transcriptional regulation by oestrogens and other mitogens. In breast cancer cells, pro- cathepsin Dproduction and secretion is much higher and its processing is altered compared to normal mammary epithelial cells in culture. In vitro , pro- cathepsin Dacts as an autocrine mitogen on breast cancer cellsand can be activated at acidic pH to degrade extracellular matrix, suggesting a role in mediating the effect of oestrogens on tumour growth and invasion. Retrospective clinical studies indicate a significant correlation between high 52-kDa cathepsin Dconcentrations in the cytosol of primary breast cancer and poor prognosis (Danish Breast Cancer Group, S. Thorpe, Copenhagen). We propose that among the proteases secreted by cancer cells, 52-kDa cathepsin Dis important both as a tissue marker in breast cancer and as a potential factor involved in carcinogenesis.