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Estrogen‐induced lysosomal proteases secreted by breast cancer cells: A role in carcinogenesis?
Author(s) -
Rochefort Henri,
Capony Françoise,
Garcia Marcel,
Cavaillès Vincent,
Freiss Gilles,
Chambon Monique,
Morisset Muriel,
Vig Françoise
Publication year - 1987
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240350103
Subject(s) - biology , autocrine signalling , cathepsin d , protease , estrogen , carcinogenesis , cathepsin , proteases , cancer cell , cancer research , endocrinology , medicine , cell culture , cancer , biochemistry , enzyme , genetics
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 man‐nose‐6‐phosphate signals. This precursor display 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.