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)

Cathepsins D, B, and L are acidic lysosomal proteinases involved in intracellular protein turnover. Increased levels of these enzymes have been reported to be indicators of aggressive tumor behavior in human and rodent tumors. In breast cancer increased levels of cathepsin D have been reported to be an independent prognostic factor in women with stage I disease. We used standard immunohistochemical techniques on formalin-fixed, paraffin-embedded tissue to examine the levels of cathepsins D, B, and L in 80 carcinomas of the breast and compared that with other indicators of aggressive tumor behavior, including stage of disease, tumor size, nuclear grade, estrogen receptor status, disease recurrence, and 5-year survival rates. Positive granular cytoplasmic staining was detected for cathepsin D in 90% of the tumors, for cathepsin B in two thirds of the tumors, and for cathepsin L in approximately one half of the tumors. Positive staining also was seen in normal breast epithelium, areas of apocrine metaplasia, stromal fibroblasts, and macrophages. Our results did not show a correlation between the expression of cathepsins D, B, and L and other indicators of aggressive tumor behavior. We conclude that the results obtained using polyclonal anticathepsin antibodies do not support the prognostic usefulness of immunohistochemical analysis of these three proteinases in tumor cells in human breast cancer.
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PMID:Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer. 808 57

A stable, tamoxifen-resistant subline, MCF-7/TAMR-1, of the human breast cancer cell line MCF-7 has been established in tissue culture after long-term treatment with 10(-6) M tamoxifen. The MCF-7/TAMR-1 cell line grows equally well in the presence and absence of tamoxifen, whereas the steroidal antiestrogens ICI 164,384 and ICI 182,780 exert profound inhibitory activity on cell proliferation, although higher concentrations are required to inhibit these cells compared to the parent cells. The MCF-7/TAMR-1 cells grown in tissue culture deviate from parent characteristics by the complete lack of expression of progesterone receptors even when grown with estradiol, by an altered tamoxifen regulation of M(r) 52,000 cathepsin D synthesis and secretion, and by lack of tamoxifen stimulation of an estradiol down-regulated M(r) 42,000 protein with presumed growth inhibitory function. MCF-7/TAMR-1 cells are estrogen receptor positive. The estrogen receptors have wild-type characteristics with respect to (a) binding of estradiol, tamoxifen, and ICI 164,384; (b) estrogen and antiestrogen regulation of the estradiol-regulated proteins pS2, M(r) 61,000 alpha 1-antitrypsin-like protein, M(r) 66,000 alpha 1-antichymotrypsin-like protein, and corresponding mRNAs; and (c) estrogen and antiestrogen regulation of a transiently transfected estrogen responsive reporter gene. We suggest that the lack of tamoxifen up-regulation of the M(r) 42,000 protein synthesis in MCF-7/TAMR-1 cells may at least partly explain the resistance to tamoxifen treatment. The sensitivity to the growth inhibitory activity of ICI 164,384 and ICI 182,780 may be ascribed to the maintenance of the pure antagonistic effect of these steroidal antiestrogens on MCF-7/TAMR-1 cells. Our results indicate that treatment with pure antiestrogens may be effective when patients become refractory to tamoxifen therapy.
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PMID:Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. 813 64

Ki-67 immunoreactivity was studied in relation to immunohistochemically assessed expression of epidermal-growth-factor receptor (EGFR), estrogen receptor (ER) progesterone receptor (PgR) and cytosolic levels of cathepsin D in advanced human ovarian adenocarcinomas, borderline and benign cystadenomas and normal ovaries. A significantly higher number of Ki-67-positive cells were found in metastatic tumors vs. primary adenocarcinomas and in the total group of adenocarcinomas vs. benign/borderline cystadenomas. Cathepsin-D levels were also significantly higher in metastatic tumors than in primary adenocarcinomas, which in turn presented higher levels than were found in normal ovaries. However, no significant difference was observed between cathepsin-D levels in malignant adenocarcinomas and borderline/benign cystadenomas. Immunohistochemically assessed expression of ER and PgR was detected in variable percentages of epithelial tumor cells, and stromal cells were occasionally positive as well. In the group of primary adenocarcinomas, 46% were ER-positive and 34% were PgR-positive, although there was no significant difference between primary and metastatic lesions with respect to ER or PgR expression. Concordance between immunohistochemically assessed ER or PgR data and cytosolic ER and PgR levels measured with enzyme immunoassay was relatively low. EGFR, immunohistochemically assessed with MAb-EGFRI, was positive in 76% of the primary and in 78% of the metastatic adenocarcinomas. A strong positive association was detected between ER and PgR, and EGFR was observed to present a weak positive correlation with Ki-67 and ER. Cathepsin-D levels were not found to be significantly correlated with the expression of ER, PgR, EGFR or Ki-67.
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PMID:Ki-67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: correlation with steroid receptors, epidermal-growth-factor receptor and cathepsin D. 818 51

Cathepsin D is an estrogen (17 beta-estradiol, E2)-inducible lysosomal protease. A putative estrogen receptor (ER)-Sp1-like sequence (GGGCGG(n)23ACGGG) has been identified in the non-coding strand of the cathepsin D promoter (-199 to -165), and electromobility shift assays of nuclear extracts from MCF-7 and HeLa cells confirm that both the ER and Sp1 protein bind to 32P-labeled ER/Sp1 oligo. For example, nuclear extracts from MCF-7 cells bind to the 32P-labeled ER/Sp1 oligo; however, ER/Sp1 binding can be decreased by selective competition with excess unlabeled estrogen responsive element and Sp1 oligos, immunodepletion with ER or Sp1 antibodies, and by treating cells with ICI 164,384, an antiestrogen which inhibits formation of ER homodimer. Moreover, E2-induced chloramphenicol acetyltransferase (CAT) activity in MCF-7 cells cotransfected with a human estrogen receptor expression plasmid and a plasmid containing an ER/Sp1 sequence cloned upstream to a thymidine kinase promoter and a CAT reporter. In cotreatment studies, ICI 164,384 inhibited E2-induced CAT activity. In contrast, E2 did not induce CAT activity in MCF-7 cells transfected with plasmids containing mutations in the ER or Sp1 segments of the ER/Sp1 oligo, thus confirming that both cognate binding sites are required for estrogen responsiveness.
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PMID:Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells. 819 46

The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 microM cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%). Progesterone receptor levels increased 3.2-fold after cadmium treatment. This induction was blocked by the anti-estrogen ICI-164,384. Progesterone receptor mRNA was also increased by cadmium, as well as cathepsin D mRNA. An in vitro nuclear transcription run-on assay showed that cadmium increased the transcription of the progesterone receptor and pS2 genes and decreased transcription of the estrogen receptor gene. These are not general effects of heavy metals, as zinc, 25 and 100 microM, did not affect progesterone receptor protein and mRNA levels. Cadmium stimulated pS2 and progesterone receptor mRNAs in a clone of MDA-MB-231 cells transfected with the human estrogen receptor, but had no effect in MDA-MB-231 cells transfected with antisense estrogen receptor. Cadmium also stimulated an estrogen response element in transient transfection experiments. These data suggest that the effects of cadmium are mediated by the estrogen receptor independent of estradiol. In addition to its effect on gene expression, cadmium induced the growth of MCF-7 cells 5.6-fold.
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PMID:Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. 820 12

A third of breast cancers are estrogen dependent and respond to endocrine therapy. The estrogen receptor (ER) was the first marker used to predict the responses to treatment, and two-thirds of ER positive tumors show a favourable response. Several estrogen-regulated proteins were further studied in a search to enhance the prediction accuracy of ER status: progesterone receptors, 24-K heat shock protein, cathepsin D, and recently pS2 protein. The pS2 gene, also named BCEI, pNR-2 [4], Md2, was first identified by two groups using differential screening of a complementary DNA library derived from a human breast carcinoma cell line (MCF-7) grown with and without estrogens. Later on two independent English groups and a Japanese group identified a gene similar to pS2. The pS2 mRNA, relatively abundant (0.8%) in the MCF-7 cell line when stimulated by estrogens, encodes a cystein-rich, 84 aminoacids peptide which is secreted by breast cancer cells. The expression of the pS2 gene, pS2 protein assays in tumor cytosols and more recently pS2 detection by immunocytochemistry, have been described in several series of breast cancers.
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PMID:Clinical significance of the estrogen regulated pS2 protein in mammary tumors. 824 Jul 4

Immunocytochemical assays for EGFR were performed on frozen sections from breast carcinomas (n = 209). Results were evaluated by computer assisted image analysis to accurately define the percentage of immunostained surface and the mean optical densities. Thirty seven percent (n = 77/209) of the tumors were EGFR positive, but about one third of them were faintly reactive (35%). No significant relationship was observed between EGFR tumor content and patient age, tumor size, histological type, histoprognostic grade, or axillary lymph node status. A negative correlation was observed with the results of estrogen receptor immunocytochemical assays and a positive correlation with immunodetectable cathepsin D and Ki 67 antigen evaluated according the same method. No correlation was found with HER-2/neu protein, aneuploidy, nucleolar organizor region distribution, and nuclear morphometry, also assessed by image analysis. These results suggest that immunocytochemical assays assessed on frozen sections and evaluated by image analysis are suitable for current and standardized evaluation of EGFR which has been previously documented as a prognostic indicator in breast carcinomas.
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PMID:Epidermal growth factor receptor in breast cancer: correlation of quantitative immunocytochemical assays to prognostic factors. 836 21

Male breast cancer is probably hormone dependent, but studies are few due to the rarity of this tumor. We have studied 21 cases of male breast cancer immunohistologically for estrogen receptor (ER) and cathepsin D (CD) expression. In carcinoma of the female breast ER expression is associated with longer patient survival and responsiveness to hormonal manipulation. Cathepsin D is an estrogen-regulated lysosomal protease with proteolytic and mitogenic properties whose presence denotes a functioning ER. In our series of male breast carcinomas 86% were ER positive and 62% were CD positive; this compares with typical figures of 50% and 66%, respectively, for female breast cancer. We observed no trends between expression of ER and CD and patient survival; immunostaining for ER and CD is unlikely to be clinically useful in carcinoma of the male breast. The high rate of ER positivity in males suggests that male and female breast carcinomas are biologically different tumors.
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PMID:Expression of cathepsin D and estrogen receptor in male breast carcinoma. 838 63

The cathepsin D (cath-D) gene, coding for a ubiquitous lysosomal aspartyl protease, is overexpressed in aggressive human breast cancers, and its transcription is induced by estrogens in hormone-responsive breast cancer cells. We have determined the structure and function of the proximal 5' upstream region of the human cath-D gene from MCF7 cells. We show that the promoter has a compound structure with features of both housekeeping genes (high G+C content and potential transcription factor Sp1 sites) and regulated genes (TATAA sequence). By RNase protection assay, we show that transcription is initiated at five major transcription sites (TSSI to -V) spanning 52 base pairs. In hormone-responsive breast cancer cells, estradiol increased by 6- to 10-fold the level of RNAs initiated at TSSI, which is located about 28 base pairs downstream from the TATA box. The specific regulation by estradiol of transcription starting at site I exclusively was confirmed by primer extension. Moreover, the same estradiol effect was observed in the ZR75-1 cell line and in MDA-MB231 estrogen-resistant breast cancer cells stably transfected with the estrogen receptor. Site-directed mutagenesis indicated that the TATA box is essential for initiation of cath-D gene transcription at TSSI. In breast cancer biopsy samples, high levels of TATA-dependent transcription were correlated with overexpression of cath-D mRNA. We conclude that cath-D behaves, depending on the conditions, as a housekeeping gene with multiple start sites or as a hormone-regulated gene that can be controlled from its TATA box.
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PMID:Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells. 841 24

The p53 protein was identified in primary breast carcinomas by specific binding of PAb1801 and PAb240 antibodies. Using sodium dodecyl sulfate electrophoresis followed by immunoblotting on nitrocellulose membrane, the p53 protein was identified in 36 nuclear fractions obtained from 60 primary breast cancers; semiquantitation of p53 was performed by densitometric scanning. The total cathepsin D content, the estrogen and progesterone receptor concentration values and the axillary lymph node involvement were also assessed. Tumors expressing p53 had significantly higher levels of cathepsin D than those in which p53 was undetectable. p53 expression was strongly associated with low or negative estrogen receptor values; progesterone receptor concentrations were also significantly higher in p53-negative tumors than in those tumors with detectable p53 levels. Finally, a significant relationship between p53 expression and lymph node metastasis was observed. It was concluded that a positive association between p53 and cathepsin D values exists which is of prognostic interest in that both cathepsin D and p53 are associated with a high tumor grade and metastatic activity.
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PMID:p53 associated with cathepsin D in primary breast cancer. 851 12


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