Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

This study investigated the prognostic value of immunohistochemically detected cathepsin D expression in 103 invasive ductal carcinomas of the breast at stages pT1 and 2. We also assessed the association between cathepsin D expression and histomorphological tumour subtypes (invasive ductal carcinoma with extensive intraductal component, multifocal tumour). Cathepsin D expression was examined at two cut-off levels (positive and highly positive) and separately identified within the epithelial and stromal component of all tumours. Positive and highly positive epithelial expression was detected in 32 (31.1%) and 20 (19.4%) patients respectively. Stromal expression was found in 35 (34%) and 19 (18.4%) cases respectively. Epithelial cathepsin D expression was associated with stage and nuclear grade, but not with lymph node or oestrogen receptor status. Positive and highly positive epithelial cathepsin D expression showed significant prognostic value for overall survival (P = 0.003 and 0.01) and recurrence-free interval (P = 0.04 and 0.02). Cathepsin D expression in stromal cells was not associated with either several established prognostic factors or survival. Multivariate analysis revealed that cathepsin D expression failed to be an independent predictor of patients' outcome. Cathepsin D expression shows no significant association with histomorphological subtypes of breast cancer. Our study supports the prognostic impact of immunohistochemically detected cathepsin D expression in the epithelial component of breast cancer.
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PMID:Prognostic value of cathepsin D expression and association with histomorphological subtypes in breast cancer. 968 94

In the last few years there has been an increased interest in treatment predictive factors in breast cancer patients. The aim of the study was to analyse the role of cathepsin D and plasminogen activator inhibitor-1 (PAI-1) expression as independent prognosticators and to assess their predictive value with respect to tamoxifen treatment. This study comprises 1851 patients with primary breast cancer diagnosed during 1988-1992. Their median age was 62 years (range: 24-91). The end-point was distant disease recurrence-free interval. Adjuvant treatment with tamoxifen was given to 1136 patients (61%). The median follow-up time was 59 months (range: 39-88). Cathepsin D content was shown to be a significant independent prognosticator in multivariate Cox analysis (P=0.02). The optimal cut-off level was 10 fmol/mg protein, other cut-off levels did not improve the results. The level of cathepsin D also appeared to predict the benefit of tamoxifen among oestrogen receptor (ER)-positive patients although this result did not reach statistical significance (P=0.09). In a multivariate Cox analysis including 497 patients PAI-1 content was shown to be a significant independent prognosticator (P=0.003) but did not appear to predict the benefit of tamoxifen treatment. The optimal cut-off level appeared to be 3 ng/mg protein, which was close to the median value 2.5 ng/mg (range: 0-51). We conclude that cathepsin D is a significant independent prognosticator and may possibly also predict the benefit of tamoxifen amongst ER-positive patients. PAI-1 was also found to be a strong independent prognosticator but no treatment interaction with adjuvant tamoxifen was found.
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PMID:The role of cathepsin D and PAI-1 in primary invasive breast cancer as prognosticators and predictors of treatment benefit with adjuvant tamoxifen. 1089 50

We assayed thymidine kinase (TK) and cathepsin D (Cath-D) in 200 breast carcinomas and we found that they were significantly correlated. This correlation was present in lymph node positive tumours, in G2 and G3, in T1 and in invasive ductal carcinomas. In addition, TK and Cath-D did not correlate with oestrogen receptor (ER) and progesterone receptor (PgR) status. We conclude that the relationship between Cath-D and TK may indicate a tumour population of high proliferation activity and invasiveness potential, related to a more aggressive phenotype, whose identification may be useful in defining prognosis.
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PMID:Co-expression of thymidine kinase and cathepsin D in 200 primary breast carcinomas. 1109 79

There is considerable enthusiasm for the prospect of using common polymorphisms (primarily single nucleotide polymorphisms; SNPs) in candidate genes to unravel the genetics of complex disease. This approach has generated a number of findings of loci which are significantly associated with sporadic Alzheimer's disease (AD). In the present study, a total of 15 genes of interest were chosen from among the previously published reports of significant association in AD. Genotyping was performed on polymorphisms within those genes (14 SNPs and one deletion) using Dynamic Allele Specific Hybridization (DASH) in 204 Swedish patients with sporadic late-onset AD and 186 Swedish control subjects. The genes chosen for analysis were; low-density lipoprotein receptor-related protein (LRP1), angiotensin converting enzyme (DCP1), alpha-2-macroglobulin (A2M), bleomycin hydrolase (BLMH), dihydrolipoyl S-succinyltransferase (DLST), tumour necrosis factor receptor superfamily member 6 (TNFRSF6), nitric oxide synthase (NOS3), presenilin 1 (PSEN1), presenilin 2 (PSEN2), butyrylcholinesterase (BCHE), Fe65 (APBB1), oestrogen receptor alpha (ESR1), cathepsin D (CTSD), methylenetetrahydrofolate reductase (MTHFR), and interleukin 1A (IL1A). We found no strong evidence of association for any of these loci with AD in this population. While the possibility exists that the genes analysed are involved in AD (ie they have weak effects and/or are population specific), results reinforce the need for extensive replication studies if we are to be successful in defining true risk factors in complex diseases.
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PMID:Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease. 1143 25

There is ample information on the clinical role of biologic factors in female breast cancer: urokinase-type plasminogen activator (uPA), its receptor uPAR, its inhibitors PAI-1 and PAI-2, cathepsin D and pS2-protein. However such reports are missing or very rare for male breast cancer. We determined the cytosolic levels of oestrogen receptor (ER), progesterone receptor (PgR), cathepsin D, pS2-protein, uPA, uPAR, PAI-1 and PAI-2 of the primary tumour tissues from 40 male breast cancer patients. The tumour levels were compared with those of 180 matched females and 4114 historic females with breast cancer. In male breast tumours the level of PgR was higher, those of uPA, PAI-1, PAI-2 and cathepsin D lower. The tumour level of ER in men was similar to those in the matched and postmenopausal women, but much higher than those in the historic women. Male breast cancer seems to be biologically different from female breast cancer. Correlation of the eight cell biologic factors with disease outcome showed that PAI-1 (p = 0.03) was the only independent predictive factor for poor prognosis in male breast cancer.
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PMID:Clinical relevance of biologic factors in male breast cancer. 1172 61

The putative role of mannose-6-phosphate/insulin-like growth factor-II receptor (M6P/IGFII-R) as a tumour suppressor and its value as a prognostic marker of breast cancer was studied in 42 benign breast diseases (BBD), 61 in situ carcinomas (CIS) and 133 invasive carcinomas. The receptor was quantified by immunohistochemistry with a computerised image analyser, using specific polyclonal IGY antibodies. The M6P/IGFII-R level varied markedly according to the different patient samples, but median values and distributions were similar in lesions and normal adjacent glands. However, the receptor level was significantly increased in high-grade ductal carcinomas in situ (DCIS) and decreased in invasive carcinomas relative to adjacent normal tissue. The M6P/IGFII-R protein concentration in invasive breast carcinomas was mostly independent of prognostic parameters: tumour size, histological grade, lymph node (N) invasiveness and oestrogen receptor alpha (ERalpha) status. The only positive correlation was with cathepsin D, the progesterone receptor (PgR) and with patients aged >60 years. These results do not support the hypothesis of a frequent and early inactivation of the M6P/IGFII-R gene in breast cancer. Clinical follow-up of patients might reveal a prognostic value for one of the cathepsin receptors.
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PMID:Mannose-6-phosphate/insulin-like growth factor-II receptor expression levels during the progression from normal human mammary tissue to invasive breast carcinomas. 1262 43

Environmental contamination with a variety of industrial products has been associated with developmental and reproductive abnormalities in wildlife species. Increasing evidence has suggested that bisphenol A (BPA) and 4-nonylphenol (NPH), two major endocrine-disrupting chemicals, might be responsible for adverse effects on humans as a consequence of ubiquitous use together with potential oestrogen-like activity. To provide insight into the oestrogen-like nature of BPA and NPH, their ability to activate a reporter gene construct via an oestrogen response element in the hormone-dependent breast cancer cell lines MCF7 and T47D was ascertained. Both compounds transactivated the endogenous oestrogen receptor (ER) alpha in a direct fashion since the anti-oestrogen 4-hydroxytamoxifen abolished the response. In addition, using steroid-receptor-negative HeLa cells engineered to express ERalpha and ERbeta and the hormone-binding domains of both ERalpha and ERbeta, BPA and NPH confirmed the direct transcriptional activity. Interestingly these properties were supported in MCF7 cells by the ability to autoregulate ERalpha expression as well as to induce its nuclear compartmentalization. We therefore evaluated by reverse transcriptase polymerase chain reaction the expression of oestrogen-controlled genes such as cathepsin D and TFF1 (formerly pS2), which were increased by both chemicals tested. The agonistic effects exhibited in all assays performed prompted the evaluation of a more complex biological response such as the proliferation of MCF7 and T47D cells. The same concentration of xenoestrogens eliciting substantial transcriptional activity significantly stimulated the proliferation of both breast cancer cell lines, although with a reduced effectiveness with respect to the natural hormone 17beta-oestradiol. The results indicate that the biological action of environmental oestrogen such as BPA and NPH should be taken into account for the potential impact on human disease-like hormone-dependent breast cancer. However, further studies are needed to clarify their bioavailability and metabolism as well as whether compound mixtures could produce noticeable effects by synergistic activity.
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PMID:Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha. 1475 35

The immunohistochemical detection of six markers of breast cancer has been compared in the present study with known prognostic factors of the disease to establish locally a standard panel of markers for the management of breast cancer. Sections of tissue of 114 consecutive breast cancer cases were studied immunohistochemically, using antibodies against oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, c-erbB2, cathepsin D, and cyclin D. Marker labelling was graded as recommended in the literature. Using the chi(2)-test, relationships were determined between marker labelling and histological type of cancer, tumour grade, tumour size, axillary lymph node status and age of patient. A p value below 0.05 was considered significant. A positive relationship was found between ER and PR and lower grades of cancer, and a negative relationship was found with medullary and atypical medullary carcinoma. The four other markers showed no relationship with grade or type of cancer. All markers showed no significant relationship with size of tumour, presence of axillary node metastasis or age of patient. There was positive correlation between c-erbB2 and cathepsin D. Our study confirms the association between ER and PR and histological type and grade of breast cancer, both known parameters of good prognosis. We found no consistent relationship between the other four markers and prognostic factors studied, other than the suggestion that c-erbB2 and cathepsin D may be useful markers for poor prognosis and can be usefully applied locally, especially in the light of the current availability of trastuzumab (Herceptin) for management of c-erbB2-positive cases. We found no relationship between the markers and tumour size, axillary lymph node status or age.
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PMID:Relationship between the expression of various markers and prognostic factors in breast cancer. 1595 51

WEB-2086 -- an antagonist of platelet-activating factor receptor (PAFR) with known anti-inflammatory, antiangiogenic and antileukaemic properties -- also proved to inhibit the proliferation in human solid tumour cell lines of different histology, and with much higher efficacy than in normal fibroblasts. A detailed analysis of WEB-2086 anticancer activity was then performed focusing on breast adenocarcinoma MCF-7 and MDA-MB-231 cells. WEB-2086-treated cells, either expressing (MCF-7) or unexpressing (MDA-MB-231) the oestrogen receptor (ER)alpha, underwent a dose-dependent growth arrest (IC(50)=0.65+/-0.09 and 0.41+/-0.07 mM, respectively) and accumulation in G(0)-G(1) phase. WEB-2086 also induced morphological and functional changes typical of mature mammary phenotype including (i) cell enlargement and massive neutral lipid deposition (best accomplished in MCF-7 cells); (ii) decrease in motility and active cathepsin D levels (mainly observed in highly invasive MDA-MB-231 cells). The expression of ERalpha was neither increased nor reactivated in treated MCF-7 or MDA-MB-231 cells, respectively. WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status. Overall, WEB-2086 can be proposed as an effective antiproliferative and differentiative agent with interesting translational opportunities to treat breast cancers in support to conventional chemotherapy.
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PMID:Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086. 1672 73

Cathepsin D was initially identified as being an oestrogen responsive protein in breast cancer cell lines. Subsequent studies have shown a role for this lysosomal enzyme in invasion and metastasis. Immunoassay and blotting studies have demonstrated a relationship between high cathepsin D levels in breast carcinomas and poor prognosis, but the converse or no relationship has been found in immunohistochemical studies. Cathepsin D from stromal cells, which will be included in tumour homogenates, may account for this difference. This immunohistochemical study of 145 breast carcinomas has used two monoclonal antibodies to cathepsin D, and considered staining of stromal cells as well as tumour cells. Some differences were found in the reactivities of the two antibodies. No relationship has been found between tumour cell reactivity and node status, grade, oestrogen receptor status and prognosis. Up to one third of carcinomas had no staining of tumour cells but a diffuse stromal cell infiltrate. Prominent stromal cell reactivity was associated with poorer survival but these tumours were predominantly poorly differentiated. However, stromal cell reactivity cannot account alone for the differences reported between different studies in relation to cathepsin D land prognosis. Other factors may include differences in detection of the different molecular weight forms, as well as quantification.
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PMID:Cathepsin-d in breast carcinomas - the role of the stromal cell component. 2160 43


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