Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.
 ...
PMID:[Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?]. 984 Oct 98

The study of several human estrogen receptor positive breast cancer cell lines has allowed characterization of a number of estrogen-induced proteins (e.g. progesterone receptor, cathepsin D, pS2 and fibulin-1 in ovarian cell lines). In primary tumours, these markers have different prognostic significance for predicting whether the tumour will be hormone responsive (e.g. pS2, estrogen and progesterone receptors) or will develop metastasis (e.g. cathepsin D). Studies of estrogen-regulated genes should also lead to new therapeutic approaches for hormone-resistant cancers. The role of estrogens as mitogens stimulating the growth of breast and ovarian cancer cell lines is well established. By contrast, their action on metastasis appears more ambiguous. Breast cancer cells without estrogen receptor (ER) are generally less differentiated and more aggressive than those containing functional ER. Moreover, the reexpression of ER by transfection in ER-negative cell lines inhibit their metastatic and invasive potential. These results suggest a protective role of ER in tumor progression. Studies of the underlying mechanisms of this effect may open new therapeutical strategies.
 ...
PMID:[Estrogen-induced genes in breast cancer, and their medical importance]. 1046

Fibulin-1 (Fbln-1) is an immunogenic breast cancer-related glycoprotein identified by serological analysis of cDNA expression library (SEREX) strategy. Here, we show that dendritic cells from two breast cancer patients elicited a CD4(+)-mediated T-cell response to Fbln-1 presentation. In both patients, an antibody response to Fbln-1 was also found. By contrast, a Fbln-1-seronegative patient and a weakly seropositive patient demonstrated no such T-cell response. Analysis of human breast cancers for Fbln-1 RNA and protein expression revealed the presence of Fbln-1C and -1D variants. Fbln-1 was detected in the cytoplasm and at the cell surface of different human breast carcinoma cell lines. Immunohistochemical analysis of 528 archival primary breast carcinomas showed the expression of Fbln-1 in 35% of the cases. When the immunohistochemical findings were compared against pathobiological information associated with each specimen, an inverse relationship between Fbln-1 and cathepsin D expression was observed (P=0.04). Furthermore, even though long-term survival was similar between Fbln-1-positive and -negative cases, the survival of Fbln-1-positive cases improved when a lymphoid infiltrate was present at the tumour site. Taken together, our findings of an Fbln-1-specific immunity and the improved survival associated with Fbln-1 expression in the presence of lymphoid infiltration point to a role of Fbln-1 in tumour immunosurveillance.
 ...
PMID:Immunological and pathobiological roles of fibulin-1 in breast cancer. 1469 54

The fibulins are a family of secreted glycoproteins that are characterized by repeated epidermal-growth-factor-like domains and a unique C-terminus structure. Fibulins modulate cell morphology, growth, adhesion, and motility. Our initial basement membrane degradome screen using Cathepsin D, a tumor microenvironment-associated protease, contained fragments of fibulin-1 and full length fibulin-5. In this report, we evaluate the antiangiogenic activity of fibulin-1 and fibulin-5. Tumor studies demonstrate that both fibulin-1 and fibulin-5 suppress HT1080 tumor growth. CD31 labeling and TUNEL assay further reveal that fibulin-1 suppression of HT1080 tumor growth is associated with diminished angiogenesis and also enhanced apoptosis of endothelial cells and tumor cells. In contrast, fibulin-5 inhibits tumor angiogenesis with a minimal anti-apoptotic affect. Cathepsin D digestion of fibulin-1 produces a fragment with nearly the same molecular weight as fibulin-5, and this fragment (named Neostatin) inhibits endothelial cell proliferation. Additionally, degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis.
 ...
PMID:Basement membrane derived fibulin-1 and fibulin-5 function as angiogenesis inhibitors and suppress tumor growth. 1822 70