Estrogen‐induced lysosomal proteases secreted by breast cancer cells: A role in carcinogenesis?

Abstract

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

“…The lysosomal aspartyl proteinase, cathepsin-D (cath-D), is over-expressed and hyper-secreted by carcinoma cells (Rochefort et al, 1987). Many independent clinical studies have shown that the cath-D level in primary breast cancer cytosol is an independent prognostic parameter correlated with the incidence of clinical metastasis and shorter survival (reviewed by Rochefort, 1992;Ferrandina et al, 1997;Foekens et al, 1999).…”

A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells

“…Like proteases acting at a neutral pH, such as the plasminogen activator and the matrix metalloproteinases, the precursors of lysosomal proteases (e.g. procathepsin-B, D, and L) are also over-expressed and hyper-secreted by carcinoma cells (Sloane and Honn, 1984;Rochefort et al, 1987;Kane and Gottesman, 1990). However, activation of these proteases requires an acidic pH which is rather found intra-cellularly in endosomes, lysosomes or phagosomes.…”

Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors

“…20 Conversely, it is secreted constitutively in ER À cell lines. 21 The mechanism of regulation of expression has been studied extensively and DNA sequences responsible for this regulation have been determined. 19,22 A strong predictive value was found for CD concentrations in breast cancer as well as many other tumor types.…”