Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein D (apo D) is a glycoprotein involved in the human plasma lipid transport system and present at large amounts in cyst fluid from women with gross cystic disease of the breast. Apo D expression in breast carcinomas was examined by immunoperoxidase staining of a series of 163 tumors. A total of 60 (36.8%) tumors were negative for apo D immunostaining, 28 (17.2%) carcinomas were weakly positive, 33 (20.2%) were moderately stained, whereas the remaining 42 (25.8%) tumors were strongly stained with the specific antibodies. No significant correlation was found between apo D content and tumor size, lymph node involvement, or biochemical parameters such as estrogen receptors, cathepsin D, or pS2 protein. However, the finding of a significant association between apo D and menopausal status of patients or differentiation grade of tumors, with apo D values being lower in tumors from premenopausal women or in poorly differentiated carcinomas, suggested a potential value of this glycoprotein as a prognostic factor in breast cancer. Preliminary analysis of relapse-free survival and overall survival in a subgroup of 152 women with a mean follow-up of 42 months confirmed that low apo D values were significantly associated to a shorter relapse-free survival and poorer survival. According to these data, we propose that apo D in combination with other well-established prognostic factors may contribute to more accurately identify subgroups of breast cancer patients with low or high risk for relapse and death.
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PMID:Expression and prognostic significance of apolipoprotein D in breast cancer. 831 Nov 15

Immunostaining of two invasion-associated proteolytic enzymes, cathepsin D (CD) and urokinase-type plasminogen activator (uPA), was assessed in cryostat sections of 86 stage-heterogeneous breast carcinomas using monoclonal antibodies. Most tumors displayed a focal and/or heterogeneous staining pattern. Overall, staining was more frequent in host-derived stromal and inflammatory cells (uPA 54%, CD 89%) than neoplastic epithelium per se (uPA 24%, CD 70%). Intense (i.e., 2+) stromal, but not neoplastic, CD was significantly correlated with nodal or systematic metastases (node negative--10% versus node positive/systemic--33%, p = 0.04). Further, cumulative staining of more than one enzyme (CD + uPA) or more than one tumor component (stroma + epithelium) correlated with metastatic disease (no metastases--35% versus metastatic--72%, p = 0.005). Neither stromal nor epithelial CD alone was significantly correlated with short-term recurrence free survival, however additive CD staining (i.e., stromal + epithelial) was strongly predictive, overall (both + -75% recurred versus both weak/negative--16% recurred, p = 0.0004) and in node positive patients (p = 0.02). We conclude that (a) enzymes putatively mediating extracellular matrix dissolution may be derived from multiple sources and (b) the metastatic capacity and/or clinical aggressiveness of breast carcinomas may reflect overall proteolytic enzyme expression, suggesting that cooperative enzyme interaction may be required for invasive growth and/or metastasis.
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PMID:Immunohistologic evaluation of invasion-associated proteases in breast carcinoma. 834 78

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 expression of cathepsin D was evaluated by immunohistochemistry on histologic sections from formalin-fixed samples in a series of 436 primary breast cancers. The fraction of cathepsin D-positive tumor cells was not related to tumor size or hormone receptor status, and only weakly related to proliferative activity, evaluated as the 3H-thymidine labeling index. Conversely, a higher fraction of positive cells was observed in node-positive than in node-negative tumors (p = 0.05). A matched comparison between immunohistochemical and immunoradiometric results on individual tumors was carried out on 100 cases and showed a significant association but with a correlation coefficient of 0.46. The agreement of results from the two assays was higher in ER- than in ER+ tumors, which sometimes showed an immunostaining limited to macrophages and normal epithelial cells. In situ evaluation has the main advantage of being specifically applicable to detection in tumor cells and allows the simultaneous determination of different biologic aspects for a more complete understanding of breast cancer biology.
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PMID:Quantitative immunohistochemical determination of cathepsin-D and its relation with other variables. 840 Mar 25

The aspartyl protease cathepsin D has been shown to be a marker of poor prognosis when found at high levels in primary breast tumors. It has been suggested that this is because the production of cathepsin D increases the invasive potential of the tumor cells, thus increasing the probability of metastasis. We have therefore conducted experiments to determine if secreted cathepsin D makes a significant contribution to the invasive phenotype of breast cancer cells in the Boyden chamber assay of invasion, which measures the ability of a cell to invade through an artificial basement membrane. Cathepsin D secretion and Boyden chamber invasiveness were measured in nine clones of the breast cancer cell line MCF-7, and no correlation was found between cathepsin secretion and invasive behavior. Invasion assays were also conducted in the presence of the aspartyl protease inhibitor pepstatin A, and no inhibition of the invasive behavior of cells was seen. Since low-pH environments are required for both the activation of pro-cathepsin D and the activity of the mature enzyme, assays were also conducted in the presence of chloroquine to neutralize the pH in the acidic compartments of the cells. This treatment did not inhibit invasiveness. Cathepsin D secretion by the breast cancer cell lines MDA-MB-231, MDA-MB-435, MDA-MB-435s, MDA-MB-468, SK-Br-3, and MCF-7-ADRr was also measured. Again, there was no correlation with invasion. In fact, cathepsin D levels were inversely correlated with aggressive behavior in vivo and in vitro in previously reported studies. These data suggest that cathepsin D secretion by tumor cells is not an important determinant of the invasiveness of the tumor cells per se. These data also reinforce the view that the poor prognosis in clinical breast cancer linked to high tumor levels of cathepsin D is probably due to high levels of cathepsin D in the stromal components of the tumor such as infiltrating inflammatory cells.
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PMID:The role of cathepsin D in the invasiveness of human breast cancer cells. 842 68

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. The serine protease urokinase-type plasminogen activator (uPA), which is elevated in solid tumors, appears to play a key role in these processes. We used enzyme-linked immunoassays (ELISA) to test for uPA antigen and its inhibitor PAI-1 in tumor tissue extracts of 247 breast cancer patients who were enrolled in a prospective study. The relation of these data to known prognostic factors and to other variables such as DNA analysis and cathepsin D was studied. Disease-free and overall survival were analyzed according to Cox's proportional hazard model. The major new finding is that breast cancer patients with either high uPA (> 2.97 ng/mg protein) or high content of the uPA inhibitor PAI-1 (> 2.18 ng/mg protein) in their primary tumors have an increased risk of relapse and death. Multivariate analyses revealed uPA to be an independent and strong prognostic factor. The impact of uPA is as high as that of the lymph node status. In node-negative patients the impact of uPA is closely followed by that of PAI-1. Since uPA and PAI-1 are independent prognostic factors, the node-negative patients could be subdivided further by combining these two variables. In this refined analysis, patients whose primary tumors have lower levels of both antigens evidently have a very low risk of relapse (93% disease-free survival at three years) in contrast to patients with high uPA and high PAI-1 (55% disease-free survival at three years). The combination of uPA and PAI-1 in our group of patients with axillary node-negative breast cancer allows us to identify the 45 percent of patients having an increased risk of relapse. Consequently, more than half of the patients had less than a 10% probability of relapse and thus would possibly be candidates for being spared the necessity of adjuvant therapy.
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PMID:Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. 843 75

The biologic rationale for the importance of cathepsin D in breast cancer is a provocative one. Cathepsin D is both an estrogen inducible and a constitutively produced protease, which may also act directly as a peptide growth factor. Thus it may play a role in tumor invasiveness, and also in driving cell proliferation. Reported clinical studies are conflicting, with some studies showing cathepsin D levels to correlate with clinical outcome, and other studies finding prognostic significance only in selected subsets of patients, if any. Thus cathepsin D is a potentially important prognostic marker whose clinical application awaits further definition.
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PMID:Evaluation of cathepsin D as a prognostic factor in breast cancer. 840 Mar 19

The family of aspartic proteinases includes several human enzymes that may play roles in both physiological and pathophysiological processes. The human lysosomal aspartic proteinase cathepsin D is thought to function in the normal degradation of intracellular and endocytosed proteins but has also emerged as a prognostic indicator of breast tumor invasiveness. Presented here are results from a continuing effort to elucidate the factors that contribute to specificity of ligand binding at individual subsites within the cathepsin D active site. The synthetic peptide Lys-Pro-Ile-Glu-Phe*Nph-Arg-Leu has proven to be an excellent chromogenic substrate for cathepsin D yielding a value of kcat/Km = 0.92 x 10(-6) s-1 M-1 for enzyme isolated from human placenta. In contrast, the peptide Lys-Pro-Ala-Lys-Phe*Nph-Arg-Leu and all derivatives with Ala-Lys in the P3-P2 positions are either not cleaved at all or cleaved with extremely poor efficiency. To explore the binding requirements of the S3 and S2 subsites of cathepsin D, a series of synthetic peptides was prepared with systematic replacements at the P2 position fixing either Ile or Ala in P3. Kinetic parameters were determined using both human placenta cathepsin D and recombinant human fibroblast cathepsin D expressed in Escherichia coli. A rule-based structural model of human cathepsin D, constructed on the basis of known three-dimensional structures of other aspartic proteinases, was utilized in an effort to rationalize the observed substrate selectivity.
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PMID:Exploration of subsite binding specificity of human cathepsin D through kinetics and rule-based molecular modeling. 844 3

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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