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)

Cathepsin D, an aspartyl protease of lysosomes, is overproduced and hypersecreted by breast cancer cells. The prognostic value of its immunoassay in breast cancer cytosol is reviewed from the first retrospective clinical studies available, which show a strong correlation between high concentrations of cathepsin D in the cytosol of primary tumor and further occurrence of metastasis. This new prognostic factor is induced by estrogen in hormone dependent breast cancer but expressed at a high level in hormone independent breast cancer and appears to be independent of other more classical factors. Its value in node negative patients varies according to the studies. In nude mice, transfection of cathepsin D cDNA into tumor cells increases their metastatic potential, suggesting that overexpression of this protease may be one of the factors responsible for metastasis in human breast cancer. The mechanism by which this protease might facilitate metastasis in vivo is still unknown, even though cathepsin D has the potential to initiate a proteolytic cascade, to degrade extracellular matrix and to liberate FGFs like growth factors from the matrix. These studies should stimulate the search for new therapeutical agents in order to inhibit cathepsin D action.
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PMID:Biological and clinical significance of cathepsin D in breast cancer. 162 26

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.
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PMID:[Mechanism of the overexpression of the cathepsin D gene in breast cancer and consequences in the metastatic process]. 182 91

Elective cervical lymphadenectomy often is performed for laryngeal carcinoma to eliminate metastatic disease that escapes clinical and radiographic detection. We investigated characteristics of the primary tumor that might predict cervical lymph node status. We obtained archival tissue from 88 laryngectomies--65 with concurrent cervical lymphadenectomies. Of the 40 clinically negative necks that were dissected, 17% showed lymph node metastasis by pathologic examination. The primary tumors were examined immunohistochemically for expression of epidermal growth factor receptor (EGFR), p53, cathepsin D, proliferating cell nuclear antigen (PCNA), and Ki-67-specific antigen, and by flow cytometry for DNA ploidy-cell cycle analysis. Seventy-seven percent of the cases showed aberrant p53 staining, 99% expressed EGFR, 40% produced cathepsin D, 29% were aneuploid, and 54% had a moderate or high synthesis phase fraction (SPF). High grade, aneuploidy, and tumor vascular invasion independently predicted cervical node metastasis (p < .04 each). Supraglottic locale (p < .16) and a raggedly infiltrating invading margin (p < .13) were weakly associated with node positivity. Advanced clinical T status, the expression of EGFR, p53, and cathepsin D, the PCNA and Ki-67 indices, and SPF did not correlate with node metastasis. The presence of cervical node metastasis predicted poor disease-free (p < .005) and overall survival (p < .04). Advanced clinical T status correlated with brief overall survival (p < .02). Tumor site, histopathologic parameters, ploidy, SPF, PCNA and Ki-67 indices, and the expression of p53, EGFR, and cathepsin D did not affect survival. The presence of vascular invasion, high grade, and aneuploidy may help identify which patients would benefit from elective cervical lymphadenectomy. The correlation of cervical lymph node status and clinical T category with survival confirms the results of previous studies.
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PMID:Cervical lymph node status and survival in laryngeal carcinoma: prognostic factors. 766 16

Bcl-2 gene product functions to prevent apoptosis in a variety of in vitro and in vivo experiments. The prognostic significance of Bcl-2 protein expression was investigated by immunocytochemistry from paraffin-embedded tissue in a series of 174 women with breast cancer, treated with radical surgery with or without regional radiotherapy, and who had been followed up for the median of 31 years or until death. A minority (25%) of cancers were entirely negative for Bcl-2 protein. Moderate to strong Bcl-2 protein expression (present in 46%) was strongly associated with several favorable prognostic features, such as a low mitotic count, high histological grade of differentiation, and lack of p53 protein expression (P < 0.0001 for each). It was also significantly associated with lack of tumor necrosis, a low S-phase fraction size, low cathepsin D expression, DNA diploidy, and the lobular histological type, but not with the primary tumor size or the axillary nodal status. Women with cancer with moderate to strong Bcl-2 protein expression had more favorable short-term (69% versus 46% alive at 5 years) but similar long-term (29% versus 33% alive at 30 years) disease-specific survival as those with cancer with weak or lacking expression. Bcl-2 protein expression did not have independent prognostic value in a multivariate survival analysis. We conclude that Bcl-2 protein is frequently expressed in breast cancer, and its expression is associated with favorable clinicopathological features.
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PMID:Bcl-2 protein expression and long-term survival in breast cancer. 797 49

Even among breast cancer patients without metastasis to axillary lymph nodes, early recurrence can occur. To determine the risk factors for early recurrence, we performed a case-control study between 32 patients with an early recurrence of breast cancer and 122 patients without recurrence, in which tumor size, age of patient and date of operation were matched. In all 154 node-negative patients, followed up over a 13.1-year median period, expression of p53, c-erbB-2 and cathepsin D in the primary tumor were studied immunohistochemically in paraffin-embedded tissues and were compared with morphologic factors such as histologic grade and invasive growth. Univariate analysis showed that nuclear p53 immunoreaction was significantly predictive of early recurrence [risk ratio (RR) 3.3]. Likewise, cathepsin D (RR 0.22) was significantly negatively associated; however, when the risk ratio was analyzed in terms of intensity of cathepsin D staining, no superior survival was found for patients with strongly positive tumors. Overexpression of c-erbB-2 protein was not associated with outcome by either univariate or multivariate analysis. As a whole, histologic grade was confirmed as being a strong predictor (RR 42.6) and multivariate analysis showed that only histologic grade was a significant risk factor for early recurrence. p53 immunoreaction was not a significant independent factor because it was closely linked to histologic grade (P = 0.002), especially to a high mitotic index (P < 0.001). Moreover, in 14 patients with "special histologic types' of invasive carcinomas and no recurrence, all were p53-negative except one medullary carcinoma. Nuclear p53 immunoreaction is useful in supporting histologic grade to detect a high-risk for early recurrence in node-negative patients who may be eligible for systemic adjuvant therapy.
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PMID:Histologic grade and p53 immunoreaction as indicators of early recurrence of node-negative breast cancer. 907 Mar 33

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
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PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

It is the ability to invade and metastasize that ultimately determines the prognosis in cancer. Comprising one of the key groups of molecules involved in invasion and metastasis are proteases such as urokinase plasminogen activator and cathepsins B, D, and L, as well as various metalloproteases. These proteases catalyze degradation of the interstitial matrix and basement membranes, allowing cancer cells to invade locally and metastasize to distant sites. If proteases are directly and causally involved in cancer spread, they have the potential to be new prognostic markers in cancer. One of the best examples of a correlation between high levels of a protease in a primary tumor and poor prognosis is urokinase plasminogen activation in breast cancer. In this malignancy, the urokinase plasminogen activator is a strong and independent prognostic marker and may be a marker for axillary node-negative disease. The urokinase plasminogen activator may also be a prognostic marker in other cancers such as gastric, colorectal, lung, bladder, cervical, and ovarian cancers. In a number of studies, cathepsin D has been shown to be a prognostic factor in breast cancer. However, results with cathepsin D, especially when immunocytochemistry is used for its detection, are conflicting. Levels of cathepsin B, cathepsin L, and certain metalloproteases may also supply prognostic data in certain cancers, but results with these proteases are still preliminary.
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PMID:Proteases as prognostic markers in cancer. 981 10

Purpose of our study was to develop a reliable model to define clinical stage I nonseminomatous germ cell tumors (NSGCT) being at low risk and at high risk for occult retroperitoneal metastases based on pathohistological and immunohistochemical parameters in order to stratify the therapeutic approach. 3-5 paraffin-embedded formalin fixed tissue blocks of 149 clinical stage I NSGCT were available from all patients and were analyzed for histopathological features associated with pathological stage: presence/absence of vascular invasion, presence/absence of tunical invasion, percentage of each histological cell type present in the primary tumor. Immunohistochemical expression of MIB-1, p53, bcl-2, cathepsin D and e-cadherin was evaluated using a semiquantitative scoring ystem. Statistical analysis was performed by univariate and multivariate logistic regression models. Percentage of embryonal carcinoma [%EC (p < 0.001)] and presence of vascular invasion [VI (p < 0.0001)] were the most significant independent risk factors associated with pathological stage II disease. Combination of %EC and VI allowed correct prediction of final pathological stage in 88% of patients. Cut-off values including both variables identified correct pathological stage in 131/149 patients (88%). Less than 45% EC and absence of VI correctly identified pathological stage I disease in 91.5%; more than 80% EC and presence of VI correctly predicted pathological stage II in 88% of the patients. %EC and presence/absence of VI appear to be reliable prognosticators to identify both patients at high risk and at low risk for occult retroperitoneal disease. P53, bcl-2, MIB-1, cathepsin D and e-cadherin did not appear to be of prognostic value in clinical stage I NSGCT.
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PMID:[Histopathologic and biological prognostic factors of clinical stage I non-seminomatous germ cell tumors. Implications for risk-adjusted therapy]. 1023 39

In 1991, our group was the first to report the prognostic strength of plasminogen activator inhibitor type 1 (PAI-1) in primary breast cancer. The prognostic impact of invasion markers PAI-1 and urokinase-type plasminogen activator (uPA) on disease-free survival (DFS) and overall survival (OS) in breast cancer has since been independently confirmed. We now report on the prognostic impact of PAI-1 and uPA after long-term median follow-up of 77 months for our cohort (n = 316). Levels of uPA, PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. S-phase fraction (SPF) was measured flowcytometrically in paraffin sections. Using log-rank statistics, optimized cutoffs were found for PAI-1 (14 ng/mg), uPA (3 ng/mg), cathepsin D (41 pmol/mg), and SPF (6%). In all patients, various factors (PAI-1, uPA, nodal status, SPF, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on DFS. In Cox analysis, only nodal status (p < 0.001, RR: 3.1) and PAI-1 (p < 0.001, RR: 2.7) remained significant. In node-negative patients (n = 147), PAI-1, uPA, and SPF had significant univariate impact on DFS, whereas in Cox analysis, only PAI-1 was significant. PAI-1 was also significant for DFS within subgroups defined by established factors. In CART analysis, uPA enhanced the prognostic value of PAT-1 and nodal status for determination of a very-low-risk subgroup. For OS, only lymph node status and PAI-1 were significant in multivariate analysis. PAI-1 levels in the primary tumor were also a significant prognostic marker for survival after first relapse in both univariate and multivariate analysis.
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PMID:Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse. 1042 5

After long-term follow-up, the prognostic impact of the following proteolytic factors associated with tumor invasion and metastasis was evaluated in 276 primary breast cancer patients: uPA (urokinase-type plasminogen activator), PAI-1 (uPA inhibitor type 1), and cathepsins B, D and L. The median follow-up of patients still alive at the time of analysis was 109 months. To date 119 patients (43%) have relapsed and 117 (42%) have died. Antigen levels of uPA and PAI-1 were determined by ELISA in detergent extracts; cathepsin B, D, and L content was determined in cytosol fractions of the primary tumor: cathepsin D by ELSA and cathepsin B and L by ELISA. In multivariate analysis (Cox model) for disease-free survival (DFS), lymph node status (p < 0.001; RR = 3.8), cathepsin L (p < 0.001; RR = 2.6) and PAI-1 (p = 0.027; RR = 1.7) were significant factors in all patients. In addition to these factors, grading was significant for overall survival (OS). In another multivariate approach, CART (Classification And Regression Trees) analysis, lymph node status (p < 0.001) turned out to be the strongest discriminator for patients at high risk of relapse. In the node-negative patient subset, PAI-1 was the strongest risk group discriminator (p < 0.001): in this subset, patients with low levels of both PAI-1 and cathepsin D had a very low relapse rate of only 3.2% compared to 39% in the remaining node-negative patients. In node-positive patients cathepsin L gave the best risk group assessment (p = 0.001). In conclusion, tumor-associated PAI-1 and cathepsins D and L provide significant, statistically independent prognostic information for DFS and OS in primary breast cancer, even after a median follow-up period of almost 10 years.
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PMID:Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer. 1076 46


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