1509

CTSD

cathepsin D;CTSD;cathepsin D

ceroid-lipofuscinosis, neuronal 10|epididymis secretory sperm binding protein Li 130P|lysosomal aspartyl peptidase|lysosomal aspartyl protease

11p15.5

protein-coding

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.

The lysosomal aspartic protease cathepsin D (cath-D) is over-expressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Cath-D over-expression stimulates tumorigenicity and metastasis. Indeed it plays an essential role in the multiple steps of tumor progression, in stimulating cancer cell proliferation, fibroblast outgrowth and angiogenesis, as well as in inhibiting tumor apoptosis. A mutated cath-D devoid of catalytic activity still proved mitogenic for cancer, endothelial and fibroblastic cells, suggesting an extra-cellular mode of action of cath-D involving a triggering, either directly or indirectly, of an as yet unidentified cell surface receptor. Cath-D is also a key mediator of induced-apoptosis and its proteolytic activity has been involved generally in this event. During apoptosis, mature lysosomal cath-D is translocated to the cytosol. Since cath-D is one of the lysosomal enzymes which requires a more acidic pH to be proteolytically-active relative to the cysteine lysosomal enzymes, such as cath-B and -L, it is open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. This review summarises our current knowledge on cath-D action in cancer progression and metastasis, as well as its dual function in apoptosis.

BACKGROUND: The c-Myb transcription factor is essential for the maintenance of stem-progenitor cells in bone marrow, colon epithelia, and neurogenic niches. c-Myb malfunction contributes to several types of malignancies including breast cancer. However, the function of c-Myb in the metastatic spread of breast tumors remains unexplored. In this study, we report a novel role of c-Myb in the control of specific proteases that regulate the matrix-dependent invasion of breast cancer cells. RESULTS: Ectopically expressed c-Myb enhanced migration and ability of human MDA-MB-231 and mouse 4T1 mammary cancer cells to invade Matrigel but not the collagen I matrix in vitro. c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. The gene coding for cathepsin D was suggested as the c-Myb-responsive gene and downstream effector of the migration-promoting function of c-Myb. Finally, we demonstrated that c-Myb delayed the growth of mammary tumors in BALB/c mice and affected the metastatic potential of breast cancer cells in an organ-specific manner. CONCLUSIONS: This study identified c-Myb as a matrix-dependent regulator of invasive behavior of breast cancer cells.

Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERalpha. In conclusion, our findings suggest that OP at 10(-6)M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of cathepsin B. These effects of mouse model resulted in an increased potential for metastasis in breast cancer. Taken together, we determined that OP can adversely affect human health by promoting cancer proliferation and metastasis through the amplification of cathepsins B and D via the ER-mediated signaling pathway.

OBJECTIVE: To investigate the relationship between Cathepsin-D(Cath-D) and the prognosis of patients with salivary adenoid cystic carcinoma (SACC). METHODS: The immunoactivity of Cath-D of 52 cases with SACC was determined by immunohistochemistry method (Streptavidin-Biotin method). The relationship between Cath-D and the histological type, clinical stage, local recurrence, distant metastasis of the tumor and survival rate of the patients with SACC were analysed. RESULTS: Statistical analysis showed that the expression levels of Cath-D were correlated positively with distant metastasis potential and clinical stage (P < 0.05), and had no significant relation with histological type, local recurrence and survival rate (P > 0.05). CONCLUSIONS: Cath-D can facilitate invasiveness and distant metastasis of SACC; evaluation of Cath-D can act as a predictor of distant metastasis of SACC and direct the clinical treatment.