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

Published online by Cambridge University Press:  05 December 2011

Henri Rochefort ,
Patrick Augereau ,
Pierre Briozzo ,
François Capony ,
Vincent Cavailles ,
Gilles Freiss ,
Marcel Garcia ,
Thierry Maudelonde ,
Muriel Morisset  and
Isabelle Touitou
...Show all authors
Henri Rochefort
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Patrick Augereau
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Pierre Briozzo
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
François Capony
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Vincent Cavailles
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Gilles Freiss
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Marcel Garcia
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Thierry Maudelonde
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Muriel Morisset
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Isabelle Touitou
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
Françoise Vignon
Affiliation:
Unité Hormones et Cancer (U 148) INSERM and Laboratoire de Biologie Cellulaire, Université de Montpellier, Faculté de Médecine, 60 Rue de Navacelles, 34090 Montpellier, France
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Synopsis

In addition to secreted growth factors, acting as autocrine or paracrine mitogens, breast cancer cells secrete 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 cell lines (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 D bearing mannose-6-phosphate signals, 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 D production and secretion is much higher and its processing is altered compared to normal mammary epithelial cells in culture. In vitro, pro-cathepsin D acts as an autocrine mitogen on breast cancer cells and 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 D concentrations 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 D is important both as a tissue marker in breast cancer and as a potential factor involved in carcinogenesis.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 95: Oestrogen and the Human Breast , 1989 , pp. 107 - 118
Copyright
Copyright © Royal Society of Edinburgh 1989

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