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

Mutation and overexpression of p53 occurs in 20-40% of breast cancers and has been shown to be an independent prognostic indicator. Recently we have demonstrated prostate-specific antigen (PSA) expression in breast tumours to be suggestive of favourable prognosis, but quantitative relationships between PSA and p53, and between these and other prognostic factors in breast cancer, have not been investigated. Time-resolved immunofluorometric procedures were used to quantify both p53 protein and PSA in 200 breast tumour extracts, which were also assayed for oestrogen (ER) and progesterone receptors (PGR), epidermal growth factor receptors (EGFR), cathepsin D and HER-2/neu, and characterised for S-phase fraction and DNA ploidy. Weak Spearman correlations were found between p53 and ER (r = - 0.18, P = 0.010), PGR (r = - 0.15, P = 0.0385) and S-phase fraction (r = 0.17, P = 0.016), while PSA was correlated only with PGR (r = 0.16, P = 0.025). Wilcoxon rank sum analysis revealed that levels of ER (P = 0.0001), PGR (P = 0.0001), S-phase fraction (P = 0.0001) and EGFR (P = 0.0014) differed significantly between the two groups categorised as p53 negative or p53 positive. Tumours classified as PSA negative or PSA positive were found to differ with respect to PGR (P = 0.0091) and S-phase fraction (P = 0.011) in a similar analysis. Contingency tables indicated significant negative associations between the status of p53 and that of ER (P = 0.003) and PGR (P = 0.001) and between PSA and S-phase fraction (P = 0.012), and positive associations between p53 and EGFR (P = 0.017), HER-2/neu (P = 0.008), S-phase fraction (P = 0.001) and aneuploidy (P = 0.007), and between PSA and both ER (P = 0.061) and PGR (P = 0.010). No significant associations were found between p53 and PSA. Our results demonstrate that the presence of p53 in breast tumours relates to several other variables which are suspected to predict aggressive tumour phenotypes and that the presence of PSA relates to variables associated with good prognosis.
Br J Cancer 1995 Sep
PMID:Immunofluorometric analysis of p53 protein and prostate-specific antigen in breast tumours and their association with other prognostic indicators. 754 16

The purpose of this study was to characterize the clinical and histological features of intraoral squamous cell carcinoma in men who were seropositive for the human immunodeficiency virus and to evaluate viral cofactors (human papillomavirus, herpes simplex virus, Epstein-Barr virus), proliferative index (proliferating cell nuclear antigen), a factor associated with invasion (cathepsin D), and mutated tumor suppressor gene and proto-oncogene products (mutated p53, c-erbB-2). Four men who were seropositive for the human immunodeficiency virus and had acquired immunodeficiency syndrome presented with painful oral lesions of variable duration. Oral cancer risk factors included heavy tobacco use (four of four), heavy alcohol use (three of four), and previous radiotherapy (one of four). The lesions consisted of ulcers (two of four), a fungating mass (one of four), and papillary erythroplakia (one of four). Incisional biopsy specimens were obtained. High-stringency in situ hybridization was performed with DNA probes to the human papillomavirus (types 6/11; 16/18; 31/33/35) and Epstein-Barr virus: Immunocytochemical studies for the herpes simplex virus, proliferating cell nuclear antigen, cathepsin D, mutated p53, and c-erbB-2 were performed. Two lesions were moderately differentiated squamous cell carcinoma, one lesion was a basaloid squamous cell carcinoma, and one was carcinoma in situ. Stage of disease at diagnosis was II (one of four), III (two of four), and IV (one of four). Three cases were positive for the human papillomavirus, one case was positive for Epstein-Barr virus, and three cases were positive for the herpes simplex virus. C-erbB-2 was focally positive in one case, and mutated p53 was positive in a separate case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraoral squamous cell carcinoma in human immunodeficiency virus infection. A clinicopathologic study. 755 63

Newly synthesized enzymes destined for lysosomal localization contain mannose 6-phosphate (Man6-P) residues, allowing interaction with Man6-P receptors (MPRs) and subsequent intracellular targeting to the lysosome. In most cultured cells, lysosomal enzymes are rapidly dephosphorylated after targeting, but in some transformed cell lines, these proteins retain the Man6-P marker. To investigate the significance of this in human malignancy, we examined the persistence of the Man6-P marker in human breast biopsy specimens using MPR derivatives as affinity probes. In one approach, extracts of frozen tissue were standardized to protein content, fractionated by SDS-PAGE, immobilized on nitrocellulose, and probed with iodinated MPR. On average, carcinomas contained 4-fold higher levels of Man6-P glycoproteins than did benign tumors or normal breast samples. In about 15% of the carcinomas, levels of Man6-P glycoproteins were highly elevated (7-10-fold). Multiple Man6-P glycoproteins were detected, suggesting a general alteration in the synthesis or processing of many lysosomal enzymes in carcinomas. In a second approach, sections of formalin-fixed breast biopsy specimens were probed with biotinylated MPR. Malignant cells in 25 of 75 carcinomas exhibited granular cytoplasmic staining in what appears to be intracellular vesicles. Staining was specifically inhibited by Man6-P and was not observed in stromal components or lymphocytes. In addition, Man6-phosphorylated proteins were not detected in the 14 normal or benign biopsy samples examined. Staining appeared to be independent of most prognostic factors examined, including p53, cathepsin D, DNA ploidy, and hormone (estrogen and progesterone) receptor status. However, positive staining was significantly associated with high histological and nuclear grades (P < 0.05) and potentially with c-erbB-2 (P < 0.10), suggesting that elevated levels of Man6-P glycoproteins are associated with the more aggressive tumors.
Cancer Res 1995 Aug 01
PMID:Increased levels of glycoproteins containing mannose 6-phosphate in human breast carcinomas. 761 83

It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease.
Int J Cancer 1995 Apr 21
PMID:Expression of tumor-associated 90K-antigen in human breast cancer: no correlation with prognosis and response to first-line therapy with tamoxifen. 761 55

The relationship between cathepsin D and other pathological or biological prognostic parameters has not yet been defined through systematic studies in breast cancer. The aim of the present investigation was to define the relationship between cathepsin D and nodal status, tumour size, steroid receptors and tumour grade in a wide patient series. Cytosol cathepsin D was assayed with an immunoradiometric assay in tumour samples from 1752 patients. A statistically significant, but not biologically meaningful association was found between cathepsin D and both tumour size and grade. Cathepsin D was significantly higher in node-positive than in node-negative tumours. However, cathepsin D is not of great use in order to predict the risk of axillary metastases in individual patients, due to overlapping of cathepsin D values between node-positive and node-negative cases. A significant, direct association was found between cathepsin D and both oestrogen receptor and progesterone receptor cytosol levels. Nevertheless, preliminary data indicate that cathepsin D and steroid receptors provide independent prognostic information.
Eur J Cancer 1995
PMID:Relationship between cathepsin D and other pathological and biological parameters in 1752 patients with primary breast cancer. 764 37

Cathepsin D from normal (Hs578Bst) and malignant (MCF7, MDA-MB-231) breast cell lines has been characterized with regard to its kinetic properties, activity levels, precursor and processed M(r) forms, and isoform composition. Normal cell cathepsin D appears to have a more neutral pH optimum (pH 3.5) than the cancer cell line (pH 3.0-3.2) and greater activity between pH values of 4.0 to 4.5. The two cancer cell lines have approximately 1.5 to 2.0-fold increased total acid protease activity and 2 to 3-fold increased pepstatin-inhibitable protease activity (i.e. cathepsin D) when compared to the normal breast cell line. Western blotting indicates that a major processed form of cathepsin D for all three cell lines occurs at 31 kDa. The cancer cell lines contain significant amounts of cathepsin D precursors of 47 and 42 kDa whereas the normal cell line contains little if any of these precursors. Isoelectric focusing indicates that the normal cell line contains approximately 50% of its total acid protease activity at pIs above 4 whereas the cancer cell lines contain 70-80% of their protease activity at such pIs. In addition, the cancer cell lines contain two to three major isoforms between pIs of 5.5 and 6.3 which were not present in the normal cell line. The isoforms from pI values of 5.5 to 7.3 for all three cell lines are 100% pepstatin-inhibitable. In addition, Western blot analysis indicates that these isoforms contain the processed 31 kDa form of cathepsin D. The combined results indicate that the two breast cancer cell lines are similar to biopsied malignant breast tissue in exhibiting altered acid protease isoform profiles with increased relative amounts of pepstatin-inhibitable and immunoreactive acid protease activity (cathepsin D) compared to normal breast tissue or cells.
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PMID:Western blotting and isoform analysis of cathepsin D from normal and malignant human breast cell lines. 764 43

In the metastatic process, proteolytic enzymes play an important role in mediating passage of the malignant cell through the cell membrane. The cathepsins are ubiquitous lysosomal proteases and are classified both functionally and according to their active site. Cathepsin D, cathepsin B and to a lesser extent other cathepsins have been described as prognostic markers in cancer. Measurements of cathepsin D in breast tissue may be significant in predicting recurrence as well as disease free and overall survival. Reported differences concerning the role of cathepsin D as a prognostic marker may be related in part to the methodology used and the employment in the assays of antibodies prepared to different portions of the molecule. The general consensus is that elevated concentrations of cathepsin D in breast cancer tissue are highly significant indicators of the potential for recurrence. Cathepsin B, which catalyzes the degradation of laminin, may play a role in the rupture of the basement membrane and may be of importance in pancreatic and colorectal cancer.
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PMID:Tissue cathepsins as tumor markers. 766 80

It has been shown that some types of tumour cells produce activated transforming growth factor beta-1 (TGF-beta 1). However, the mechanism for the activation of TGF-beta 1 derived from tumour cells has not been fully elucidated. The present study was undertaken to characterise an activator of latent TGF-beta 1 secreted from a human gastric cancer cell line, KATO-III. Western blot analyses using antibodies for TGF-beta 1, latency associated peptide (LAP) and latent TGF-beta 1-binding protein (LTBP) revealed that, in the cell lysate of KATO-III, TGF-beta 1 protein was expressed as a small latent complex of TGF-beta 1 and LAP. This was also confirmed by a gel chromatographic analysis of the cell lysate obtained from KATO-III. A 2.5 kb transcript of TGF-beta 1 mRNA was detected in KATO-III cells by Northern blot analysis. A gel chromatographic analysis of the conditioned medium from KATO-III cells revealed, in addition to the active form of TGF-beta 1, a factor which activated latent TGF-beta 1 from NRK-49F cells at fractions near a molecular size of 65,000. This factor was inactivated by heat (100 degrees C), acidification, trypsin and serine protease inhibitors. TGF-beta 1 activity in KATO-III cell lysate was not detected in the untreated state, but potent TGF-beta 1 activity was detected after acid treatment. These results suggest that KATO-III releases not only a latent TGF-beta 1 complex but also a type of serine protease, different from plasmin, plasminogen activator, cathepsin D, endoglycosidase F or sialidase, which activates the latent TGF-beta 1 complex as effectively as acid treatment.
Br J Cancer 1995 Sep
PMID:Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. 766 80

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
Cancer Res 1995 Oct 01
PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

We evaluated levels of mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) RNA in 37 breast cancer tumors by quantitative in situ hybridization using a computer-aided image analyzer and compared them to cathepsin D RNA and protein levels in the same tissues. Breast cancer cells expressed more cathepsin D and M6P/IGFII-R RNA than fibroblasts in the same tumors. We found a significant increase of cathepsin D RNA (P = 1 x 10(-5)) and M6P/IGFII-R RNA (P = 0.02) in breast cancer cells compared to epithelial cells of benign mastopathies. There was a positive correlation (r = 0.65; P = 1 x 10(-5)) between M6P/IGFII-R and cathepsin D RNA levels measured on serial sections. This contrasted with the inverse relationship of these 2 RNA species in breast cancer cell lines where estrogen down-regulates M6P/IGFII receptor RNA levels. Moreover, in vivo we found no correlation between the M6P/IGFII-R RNA level and menopausal or estrogen receptor status, suggesting that the in vivo regulation of M6P/IGFII-R RNA differs from its in vitro regulation in cell lines. The M6P/IGFII-R RNA level was not correlated with cathepsin D status, histological grade, and tumor size but was significantly higher in lymph node-positive tumors (P = 0.047). The M6P/IGFII-R could therefore be an additional parameter to predict aggressive breast cancers, complementing cathepsin D assays and other more classical prognostic parameters.
Cancer Res 1993 Jun 15
PMID:Correlation between mannose-6-phosphate/IGFII receptor and cathepsin D RNA levels by in situ hybridization in benign and malignant mammary tumors. 768 51


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