Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cathepsin D is an acidic lysosomal protease present in all cells. In estrogen receptor positive and negative breast cancer cell lines, the mRNA coding for pro-cathepsin D is overexpressed and sorting and maturation of the pro-enzyme are altered, leading to accumulation of the active proteinase in large endosomes and to secretion of the precursor (52K protein). In MCF7 cells, the cathepsin D mRNA is induced directly and transcriptionally by estrogens and indirectly by growth factors. In vitro, pro-cathepsin D is an autocrine mitogen on breast cancer cells and can be auto-activated to degrade extracellular matrix and proteoglycans and to activate other proteinases in acidic microenvironments. In patients, there is a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and development of metastasis. This marker is independent of other prognostic factors and appears to be particularly useful in lymph node-negative tumors. These results suggest that overexpression and possible derouting of cathepsin D plays an important role in invasion and metastasis of breast cancer.
Breast Cancer Res Treat 1990 Jul
PMID:Cathepsin D in breast cancer. 220 45

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the growth of estrogen-responsive MCF-7 human breast cancer cells in the presence of 17 beta-estradiol was determined. After treatment with 17 beta-estradiol (1 nM), TCDD (10 nM) and 17 beta-estradiol (1 nM) plus TCDD (10 nM) the cells were monitored daily for cell growth and DNA content for 7 days. The results showed that TCDD inhibited cell proliferation and DNA content of untreated cells and inhibited the 17 beta-estradiol-stimulated cell proliferation and increase in cellular DNA content. In contrast, TCDD did not effect the growth of estrogen non-responsive MDA-MB-231 human breast cancer cells. TCDD (0.1-10 nM) also caused a concentration-dependent decrease in the 17 beta-estradiol-induced proliferation in MCF-7 cells. The effects of TCDD on the 17 beta-estradiol-induced secretion of the 52-kDa protein (i.e. procathepsin D), the 34-kDa (cathepsin D) and 160-kDa proteins were also determined in the MCF-7 and MDA-MB-231 human breast cancer cell lines. The levels of the proteins were determined by autoradiographic analysis of the incorporation of [35S]methionine into the secreted proteins which were separated by denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Treatment of MCF-7 cells with 17 beta-estradiol (1 nM), TCDD (10 and 100 nM) and 17 beta-estradiol (1 nM) plus TCDD (10 nM) resulted in levels of the 52-kDa protein which were 497, 63.6, 98.1 and 66.3%, respectively, of the corresponding levels observed in control (untreated) cells. Using the same concentrations, the levels of the 34-kDa protein secreted into the media were 372, 42.3, 64.0 and 43.8% of control values, respectively, and the corresponding levels of the 160-kDa protein were 381, 52.9, 71.2 and 76.6% of the control values, respectively. In contrast, treatment of MDA-MB-231 cells with 17 beta-estradiol (1 nM), TCDD (10 and 100 nM) and 17 beta-estradiol (1 nM) plus TCDD (10 nM) resulted in a 31-39% reduction in the secretion of the 52-kDa protein however these effects were not statistically different from the control values. In addition, the treatments did not cause any significant effects on the secretion of the 34- and 160-kDa proteins by MDA-MB-231 cells. These results clearly confirm and extend the range of antiestrogenic effects caused by TCDD in estrogen-responsive MCF-7 cells and indicate that the MDA-MB-231 cells are not responsive to the antiestrogenic effects of TCDD.
 ...
PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell growth and the secretion of the estrogen-induced 34-, 52- and 160-kDa proteins in human breast cancer cells. 227 56

Cathepsin D, an aspartic lysosomal proteinase, is overexpressed by breast cancer cells and highly correlated with the occurrence of metastasis in patients. We used an adenovirus transformed rat cell line that does not secrete cathepsin D, to study the consequences of transfecting human cathepsin D cDNA. Overexpression of human cathepsin D in stable transfectant clones, results in higher initial growth rates in low serum conditions, overgrowth at high cell densities resulting in stellate aggregates, and greater anchorage-independent growth in soft agar. The metastatic activity (mostly in liver) of cathepsin D clones injected into athymic mice was significantly higher than that of control clones. These results show that overexpression of cathepsin D increases the transformed phenotype of malignant cells in vitro and their metastatic potency in vivo.
 ...
PMID:Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency. 228 99

We investigated the possibility that cathepsin D, an estrogen-induced lysosomal protease, might have value as a prognostic factor in breast cancer by studying frozen tissue specimens from 397 patients. We measured the 34-kd mature form of the enzyme by Western blot assay and densitometry. Among 199 patients with node-negative disease, but not among 198 with node-positive disease, high levels of cathepsin D proved to be a significant predictor of reduced disease-free survival (median follow-up, 64 months), either as a continuous variable (log cathepsin D; P = 0.018) or as a dichotomous variable with an optimized cutoff point (P = 0.0001). Results were similar for overall survival (P = 0.009 and 0.0001, respectively). Relating the level of cathepsin D to other prognostic factors in the patients with node-negative disease, we found an association with aneuploidy but none with estrogen or progesterone receptors, tumor size, or the age of the patient. In multivariate analyses, a high level of cathepsin D was the most important independent factor in predicting shorter disease-free and overall survival in patients with node-negative disease. As compared with the risk in women with low levels of cathepsin D, the relative risk of tumor recurrence was 2.6 (95 percent confidence interval, 1.6 to 4.4) and the relative risk of death was 3.9 (95 percent confidence interval, 2.1 to 7.3) among those with high levels of cathepsin D. For disease-free survival, cathepsin D status was predictive of outcome primarily among those with aneuploid tumors; the actuarial five-year recurrence rates of aneuploid tumors were 60 percent among women with high levels of cathepsin D and 29 percent among those with low levels, as compared with 22 percent for all diploid tumors. We conclude that cathepsin D may be an independent predictor of early recurrence and death in node-negative breast cancer.
 ...
PMID:Cathepsin D and prognosis in breast cancer. 234 29

We have earlier described a monoclonal antibody (323/A3) against a Mr 43,000 surface glycoprotein of MCF-7 human breast cancer cells which shows considerable specificity for primary and metastatic breast tumors (Cancer Res., 46: 1306-1317, 1986). Here we report the occurrence of the 323/A3 antigen in a large cohort of primary breast tumors (m = 384) and its interrelationship with several clinically important variables. Frozen, stored tumor tissues were examined by a Western blot procedure, and the level of 323/A3 protein in individual tumors was calculated in arbitrary units based on the integrated Mr 43,000 signal in tumors compared with an MCF-7 internal standard. Thirty-six % (139 of 384) of tumors were found to be positive for 323/A3. Higher frequencies of 323/A3 protein were found in tumors larger than 2 cm (P = 0.03), tumors with infiltrated lymph nodes (P = 0.01), and tumors without estrogen receptor (P = 0.006). No significant relationship was found with patient age, menopausal status, or progesterone receptor status. Of the newer clinical determinants proliferative rate (% S phase), DNA ploidy, and the lysosomal protease cathepsin D, but not the HER-2/neu oncogene protein, were significantly correlated with 323/A3. The presence of 323/A3 protein was also related to increased recurrence (P = 0.003) and mortality (P = 0.036) after primary treatment. As an exposed surface antigen, this glycoprotein might be a useful target in radioimaging and immunotherapy of some human breast tumors, especially those having large size, infiltrated lymph nodes, deficient estrogen receptor, high proliferative rate, abnormal DNA content, and high levels of cathepsin D, all of which are ominous indicators of tumor behavior.
 ...
PMID:Association of the 323/A3 surface glycoprotein with tumor characteristics and behavior in human breast cancer. 233 24

Cathepsin D, a lysosomal protease, is induced by estrogens in hormone responsive breast cancer cells, by progesterone in normal endometrium and expressed at high constitutive levels in estrogen receptor (ER)-negative cells. To investigate whether ER is the only transacting factor missing in ER negative cells to obtain estrogen regulation, we transfected an ER cDNA expression vector (HEO) into ER-negative Hela cells and showed that it could recover estrogen sensitivity for cathepsin D gene expression but not for cell growth regulation. These results show i. that the expression of an endogenous gene in humans can be stimulated by estradiol after ER supplementation, indicating that Hela cells contain sufficient amounts of the other transcription factors required for cathepsin D estrogen inducibility; ii. that cathepsin D expression is stimulated by estrogens in this cervix cancer cell line, as it is in the ER-positive breast cancer cells, which contrasts with its regulation by progesterone in normal endometrial cells.
 ...
PMID:Stable transfection of the estrogen receptor cDNA into Hela cells induces estrogen responsiveness of endogenous cathepsin D gene but not of cell growth. 235 Mar 35

In breast cancer cell lines, pro-cathepsin D is synthesized in excess and abnormally processed, resulting in its slower maturation and increased secretion into the culture medium. Since this lysosomal protease is only active at acidic pH, we have searched for acidic compartments other than lysosomes where cathepsin D might be active when MCF7 cells are plated on corneal extracellular matrix. We found large acidic intracellular vesicles (1.5 to 20 microns in diameter) by acridine orange and 3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine staining, two fluorescent probes which reveal acidic compartments. These vesicles were actively acidified. They were 2- to 20-fold more abundant in MCF7 breast cancer cells and primary cultures of human breast cancers cells than in primary cultures of normal mammary epithelial cells. In living MCF7 cells, high resolution video-enhanced microscopy showed that these vesicles were mobile and intracellular. Double immunolocalization indicated that they contained mature cathepsin D (but no detectable pro-cathepsin D) and endocytosed extracellular material. This material (dextran, transferrin, and extracellular matrix) and the association with other lysosomal enzymes varied according to the vesicles, suggesting their heterogeneity (large endosomes or phagosomes). We conclude that, in breast cancer cells, cathepsin D may digest intracellularly phagocytosed and/or endocytosed extracellular matrix in large acidic vesicles. We propose that the higher expression of cathepsin D associated with the increased number of large acidic vesicles in breast cancer cells may facilitate digestion of basement membrane and consequently metastasis.
 ...
PMID:Cathepsin D in breast cancer cells can digest extracellular matrix in large acidic vesicles. 239 69

The Mr 52,000 estrogen-induced protein secreted by MCF7 cells has been identified as a procathepsin D (procath D), which increases cell growth in vitro, may stimulate invasiveness by digesting extracellular matrix and appears to be a tissue marker for predicting relapses in breast cancer patients. The protease is also present within mammary cells as Mr 48,000, 34,000, 14,000 mature forms that were also recognized by the previously described antibodies to the Mr 52,000 protein (M. Garcia, F. Capony, D. Derocq, D. Simon, B. Pau, and H. Rochefort, Cancer Res., 45: 709-716, 1985). Using selective screening with a [35S]methionine-labeled MCF7 cell lysate, we have now isolated two new monoclonal antibodies interacting exclusively with the Mr 52,000 procath D. The two monoclonal antibodies, M2E8* and D9H8*, purified from ascitic fluids are IgG1. Their respective Kds for Mr 52,000 procath D are 0.96 and 0.18 nM. They are directed against two separate domains of the proenzyme that differ from the three domains of previously described antibodies. They both interact with the deglycosylated protein and recognize the autoactivated secreted proenzyme (Mr 51,000), which is devoid of the first part of the NH2-terminal end. By immunodetection of cathepsin D proteolytic activity in plasma, these two antibodies were found to recognize selectively human cathepsin D but not the cathepsin D of other species (rat, mouse, rabbit, goat, and horse) whereas antibodies to mature cathepsin D were less species specific. Using sequential passages on concanavalin A-Sepharose and Sepharose matrices coupled to antibodies to the precursor and antibodies to the mature cathepsin D, we separately purified to homogeneity the Mr 52,000 procath D form and its processed cellular forms, whose biological activities can now be assessed independently. The two monoclonal antibodies were also shown to inhibit the uptake and processing of the Mr 52,000 cathepsin D in MCF7 cells (mostly D9H8*) and to decrease its proteolytic activity, mostly on extracellular matrix (M2E8*). These two monoclonal antibodies are therefore new tools for studying the function, regulation, cellular processing, and localization of procath D as well as the clinical significance of its concentration in normal and tumoral mammary epithelial cells.
 ...
PMID:Characterization and properties of two monoclonal antibodies specific for the Mr 52,000 precursor of cathepsin D in human breast cancer cells. 245 53

We developed a solid-phase two-site immunoenzymometric assay (IEMA) of the estrogen-induced 52-kDa cathepsin D (EC 3.4.23.5) and its processed forms (48-kDa and 34-kDa proteins) in cytosols of breast cancer tissues, using two monoclonal antibodies directed against two different epitopes of these antigens. The first antibody is bound to a polystyrene microtiter well; the second is labeled with alkaline phosphatase. The assay involves a simultaneous incubation of the antigen with both antibodies, because we observed signal loss during sequential incubations. Alkaline phosphatase was chosen because other enzymes (peroxidase, beta-galactosidase) were inhibited by cytosol extraction buffers. The measurable range of 52-kDa-related proteins is from 0.3 to 6 nmol/L with precision (CVs) within and between runs of 3.9% and 15.8%, respectively. The sensitivity, accuracy, and rapid turnaround time of the two-site IEMA should facilitate the clinical evaluation of this new marker in oncology.
 ...
PMID:Two-site immunoenzymometric assay for the 52-kDa cathepsin D in cytosols of breast cancer tissues. 246 20

A precursor form of cathepsin B (Mr 45-47 kd) was purified from ascitic fluids of patients with ovarian adenocarcinomas. Following pepsin activation, this precursor produced a 33 kd cathepsin B-like proteinase closely related to lysosomal cathepsin B. A similar activation was found using the 52 kd pro-cathepsin D secreted by the MCF7 human breast cancer cells. This activation was a time, dose and pH dependent process. These results suggest that the 52 kd pro-cathepsin D may be involved in the early steps of the "metastatic cascade", activating pro-cathepsin B in an acidic environment.
 ...
PMID:[Pro-cathepsin D can activate in vitro pro-cathepsin B secreted by ovarian cancers]. 250 Feb 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>