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Cathepsin-D: A novel approach to breast cancer Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it is estimated that well over 1 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Some cancers, notably of the breast and prostate, have 5-year survival rates in excess of 80%. However once tumors metastasize, disease is not usually curable. The development of therapeutic strategies for the prevention and treatment of metastatic cancers thus represents a key priority for the pharmaceutical industry. 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, INSERM researchers 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 cathepsin-D levels 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. These data provide the first evidence on the essential role of cathepsin-D in breast cancer, and support the development of cathepsin-D-targeted therapies. To our knowledge cathepsin-D blockers are not in pharmaceutical development and exploiting these findings should therefore give rise to a highly novel approach to the treatment of breast cancer. Entry date October, 2002 Adapted from Glondu et al, Oncogene 2002 Aug 1;21(33):5127-34
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