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

Oncogene volume 21, pages 5127–5134 (2002)Cite this article

Abstract

Overexpression of cathepsin-D in primary breast cancer has been associated with rapid development of clinical metastasis. To investigate the role of this protease in breast cancer growth and progression to metastasis, we stably transfected a highly metastatic human breast cancer cell line, MDA-MB-231, with a plasmid containing either the full-length cDNA for cathepsin-D or a 535 bp antisense cathepsin-D cDNA fragment. Clones expressing antisense cathepsin-D cDNA that exhibited a 70–80% reduction in cathepsin-D protein, both intra- and extracellularly compared to controls, were selected for further experiments. These antisense-transfected cells displayed a reduced outgrowth rate when embedded in a Matrigel matrix, formed smaller colonies in soft agar and presented a significantly decreased tumor growth and experimental lung metastasis in nude mice compared with controls. However, manipulating the cathepsin-D level in the antisense cells has no effect on their in vitro invasiveness. These studies demonstrate that cathepsin-D enhances anchorage-independent cell proliferation and subsequently facilitates tumorigenesis and metastasis of breast cancer cells. Our overall results provide the first evidence on the essential role of cathepsin-D in breast cancer, and support the development of a new cathepsin-D-targeted therapy.

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Acknowledgements

We thank M Gleizes and AM Cathiard for technical assistance and JY Cance for photographs and drafting the figures. This work was supported by the University of Montpellier I, the ‘Institut National de la Santé et de la Recherche Médicale’, the ‘Association pour la Recherche sur le Cancer’, and the ‘Institut de Recherches Servier’. M. Glondu is a recipient of the ‘Ligue Nationale Contre le Cancer, Comité de l'Hérault’ fellowship.

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  1. INSERM U540 ‘Endocrinologie Moléculaire et Cellulaire des Cancers’, Université de Montpellier 1, 60 rue de Navacelles, 34090, Montpellier, France

    Murielle Glondu, Emmanuelle Liaudet-Coopman, Danielle Derocq, Nadine Platet, Henri Rochefort & Marcel Garcia

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  1. Murielle Glondu
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  2. Emmanuelle Liaudet-Coopman
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  3. Danielle Derocq
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  4. Nadine Platet
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  5. Henri Rochefort
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  6. Marcel Garcia
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Correspondence to Marcel Garcia.

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Glondu, M., Liaudet-Coopman, E., Derocq, D. et al. Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells. Oncogene 21, 5127–5134 (2002). https://doi.org/10.1038/sj.onc.1205657

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