[Mechanism of the overexpression of the cathepsin D gene in breast cancer and consequences in the metastatic process].
Cathepsin D, an acidic protease normally acting in lysosomes, is overproduced both in vitro and in vivo in most breast cancer cells. The mechanism of gene regulation by estrogens and the biological and clinical significance of this overexpression in metastasis are reviewed. In MCF7 cells, cathepsin D is specifically and directly induced by estrogens and also induced by growth factors (EGF, IGF-I and bFGF), but this induction is dependent upon de novo protein synthesis. The mechanism of estrogen induction involves EREs located upstream from the gene. Our laboratory cloned the promoter region (-4kb) of cathepsin D of MCF7 cells and found EREs located in the proximal 5' region of the gene. In MDA-MB231 and BT20 cells, cathepsin D is overexpressed but not regulated by estrogens. Total cathepsin D concentration were assayed by IRMA in breast cancer cytosol routinely prepared for receptor assays. Several retrospective clinical studies indicate a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and further development of clinical metastasis. High cathepsin D concentration in the primary tumor may be either a consequence, or more likely a cause, of metastasis. Transfection experiments using cDNA-cathepsin D in rat tumoral cells facilitates their metastatic potential in nude mice (Garcia et al., Oncogene, 1990, 5, 1809-1814). The mechanism of cathepsin D action in facilitating metastasis is unknown and may involve proteolytic activity in an acidic compartment, and/or interaction with the Man 6P/IGFII receptor.
Rochefort
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Unité Hormones et Cancer (U 148) INSERM, Faculté de Médecine, Montpellier, France.
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002402:Cathepsin D / Q000235:genetics*; D003600:Cytosol / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics*; D011379:Prognosis
D002402:Cathepsin D
Mécanismes de l'hyperexpression du gène de la cathepsine D dans les cancers du sein et conséquences dans le processus métastatique.