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

When cultured in-vitro, originating from different breast cancer patients, tumor cells, identified histologically as carcinoma cells, varied in their proliferation patterns and cell morphology. If exposed for brief periods to vibrio cholera neuraminidaes (VCN), the amount of sialic acid released from the cells varied from one culture to another and increased with higher enzyme concentrations. If exposed to trypsin, the amount of released proteins varied also from one culture to another. Significant difference was observed between the effect of VCN or collagenase on normal and neoplastic cell cultures. Whether human or murine cell cultures, the cell-free media harvested from cultures of neoplastic cells containing high concentrations of collagenolytic-caseinolytic-fibrinolytic and esterolytic activities. Two effects of concanavalin A (Con A) have been distinguished on thymidine incorporation, the first is a decrease in the maximal thymidine uptake, whereas the second is a shift to the maximum thymidine uptake to higher Con A concentrations. At low concentrations, alpha-1-antitrypsin (AAT) had no effect, but at high concentrations it inhibited 3H-thymidine uptake. At low concentrations human profibrinolysin inhibited and at higher concentration sit enhanced uptake of the labeled precursor. Therefore, the collagen olytic caseinolytic-fibrinolytic enzyme is a pacemaker for proliferation of human mammary carcinoma cells.
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PMID:Human mammary carcinoma cells. The enzyme pacemaker profibrinolysin. 31 26

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. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.
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PMID:Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. 151 91

This study reports the characterization of a breast cancer-associated antigen identified by murine monoclonal antibody (MoAb) RCC-1 (formerly called 24-17.1). Immunoperoxidase staining indicated that RCC-1 recognized an antigen highly expressed in malignant tumours of breast origin, and no reactivity was noted with connective tissue, muscle or lymph nodes, which is an important consideration in its successful use in immunolymphoscintigraphy. The RCC-1 was shown to consist of 94,000 dalton disulfide-bonded dimers which were shown to be different from the transferrin receptor. In addition, the antibody RCC-1 did not react with components of human milk or with an antigenic peptide derived from the core protein of a mammary mucin. Chemical treatment and enzymatic digestion suggested that the epitope recognized by antibody RCC-1 was protein as it was resistant to neuraminidase and periodate treatment but was sensitive to trypsin. The RCC-1-defined antigen detects a novel breast cancer associated antigen.
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PMID:Characteristics of a breast cancer-associated antigen defined by RCC-1 antibody. 169 83

The ability of DNA to allosterically alter the conformation of the estrogen receptor's (ER) steroid binding domain was investigated. Using dissociation kinetics we observed that when DNA was bound to the DNA binding domain of the rat uterine ER the rate of estrogen dissociation from the steroid binding domain increased almost 2-fold. This change in the rate of estrogen dissociation depended on the concentration of DNA used and correlated with the thermodynamic binding affinities (Kd) of the ER for two different DNA sequences. We were unable to detect a DNA-induced change in the trypsin cleavage pattern of the amino terminal end of the ER. Using a whole cell dissociation kinetic assay with MCF-7 breast cancer cells we observed a 7-fold slower rate of estrogen dissociation from the ER within the cell than from the ER in vitro. This suggests that additional factors, other than DNA binding, may modify the steroid binding domain within the cell. We conclude that DNA can allosterically modulate the structure of the steroid binding domain of the ER, and we hypothesize that this conformational change may be necessary for the full transcriptional activity of the ER.
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PMID:DNA allosterically modulates the steroid binding domain of the estrogen receptor. 173 Jul 20

Tumor cell invasion and metastasis is a multifactorial process, which at each step may require the action of proteolytic enzymes such as collagenases, cathepsins, plasmin, or plasminogen activators. An enzymatically inactive proenzyme form of the urokinase-type plasminogen activator (pro-uPA) is secreted by tumor cells which may be converted to an enzymatically active two-chain uPA-molecule (HMW-uPA) by plasmin-like enzymes. Action of proteases on pro-uPA may generate the enzymatically active or inactive high-molecular-weight form of uPA (HMW-uPA). Some proteases (plasmin, cathepsin B and L, kallikrein, trypsin or thermolysin) activate pro-uPA by cleaving the peptide bond Lys158 and IIe159. Other proteases (elastase, thrombin) cleave pro-uPA at different positions to yield enzymatically inactive HMW-uPA. HMW-uPA may be split into the enzymatically active LMW-uPA and the enzymatically inactive ATF (amino terminal fragment). ATF may be cleaved between peptide sequence 20 and 40 within the receptor binding domain of uPA (GFD). Such impaired ATF does not bind to uPA-receptors. Action of the bacterial endoproteinase Asp-N from Pseudomonas fragi mutant on pro-uPA or HMW-uPA, however, generates intact ATF which efficiently competes for binding of HMW-uPA or pro-uPA to receptors on tumor cells. High uPA-antigen content (pro-uPA, HMW-uPA, or LMW-uPA) in breast cancer tissue (not in plasma) indicates an elevated risk for the patient of recurrences and shorter overall survival. Thus pro-uPA/uPA-antigen content in breast cancer tissue serves as an independent prognostic parameter for the outcome of the disease. Cathepsin D is also an independent prognostic factor for recurrences and overall survival. High content of cathepsin D in breast cancer tumors is, however, not correlated with elevated levels of pro-uPA/uPA indicating that synthesis and release of cathepsin D and pro-uPA/uPA are independent events.
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PMID:Biological and clinical relevance of the urokinase-type plasminogen activator (uPA) in breast cancer. 180 51

Protein from hog which is recognized by human monoclonal antibody (HB4C5), generated from a patient with large cell lung carcinoma, was identified as carboxypeptidase A by comparison of the protein with carboxypeptidase A in enzymatic activity, immunologic reactivity, and amino acid sequence. Carboxypeptidase A activity was also found in human cancer tissue, and purified antigen from cancer tissue recognized by the antibody HB4C5 was reacted with rabbit anti-carboxypeptidase A serum, indicating that carboxypeptidase A is an antigen of HB4C5. Since large amounts of carboxypeptidase A can be obtained from porcine sources, a simple method for its purification was established. The fraction which was most reactive with HB4C5 was obtained from acetone powder of porcine pancreas by successive applications of water extraction, ammonium sulfate precipitation, trypsin treatment, and Mono Q column chromatography. Its apparent molecular weight was 40,000, according to SDS polyacrylamide gel electrophoresis. When the reactivity of IgG in sera with the purified carboxypeptidase A was measured, the detection rates for lung, ovary, larynx, uterus, and liver cancer were more than 50%, while the rates for stomach and breast cancer were around 30%, and pancreatic cancer, benign diseases, and normal controls were minimally detected.
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PMID:Serodiagnosis of cancer using porcine carboxypeptidase A as an animal antigen recognized by human monoclonal antibody HB4C5. 187 99

The precise origin of breast cyst fluid remains obscure. Molina has presented evidence that type II cysts (high Na/K ratio) may be transudative, that is, partly derived from plasma elements which enter through gap junctions, while Type I cysts (high K/Na ratio) are primarily secretory. In transudative cysts, plasma protease inhibitors may be present, but the balance between protease and its inhibitors may fluctuate as a result of as yet undetermined circumstances. An imbalance between the protease activity of cyst fluid and its inhibitors may be involved in the pathogenesis of breast gross cystic disease. Accumulation of protein fragments with resistant bonds would produce an elevated oncotic pressure causing a shift of fluid into the cyst capsule. Albumin is a good substrate for the protease, which may account for its low concentration in cyst fluid. The major protease fraction closely corresponds to the progesterone binding protein (GCDFP-24) described by Haagensen. Affinity columns containing aprotinin or benzamidine ligands retain the protease which can then be eluted with 0.5 M NaCl. The HD1 protease and progesterone binding protein are either tightly complexed or are the same protein. Cyst fluid is a complex mixture of biomolecules. If the progesterone binding protein is a protease, many questions must be answered concerning the influence of cyst fluid steroids, lipids, anions, and cations on enzyme action. Determination of the amino acid sequence of HD1 may help elucidate the source of the enzyme and its relationship to other tissue proteases. Human plasma contains inhibitors of this protease activity. When pooled, dialyzed plasma was mixed with pooled, dialyzed cyst fluid, the ratio of plasma/cyst fluid at which all activity was inhibited was 6/1. A comparison of the rate of cleavage of three 14C-protein substrates shows that cyst fluid proteases cleave in a characteristic manner, distinct from either trypsin or calpain. A simple method for semiquantitative estimation of protease activity in cyst fluid is described which utilizes prestained Coomassie blue-albumin containing agarose gel plates. All cyst fluids tested had protease activity but showed variability in their ability to cleave 14C-albumin by a factor of 4. There is much direct and indirect evidence that proteases are involved in the cancer process. In view of the higher than normal incidence of breast cancer in women who have had gross cystic breast disease, the possibility exists that an imbalance between these proteases and their inhibitors is somehow involved.
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PMID:Cyst fluid proteases. 211 67

pS2 is a human gene whose transcription is directly triggered by estrogen in human breast cancer cells (MCF-7). We described here the complete primary structure of the pS2 gene product. The pS2 protein purified from conditioned medium of MCF-7 cells was S-pyridylethylated and digested with TPCK-trypsin. Five major fragments were obtained by reverse-phase HPLC. Amino acid sequence analysis of these tryptic peptides established that the pS2 protein comprises a 60-amino acid polypeptide. The sequence of the pS2 protein was completely identical to that deduced from the nucleotide sequence of the pS2 gene, if the signal polypeptide is excluded. Furthermore, two cDNA clones encoding an 84-amino acid precursor pS2 protein were isolated from a cDNA library which was constructed with RNA from MCF-7 cells cultured in the presence of estrogen. The nucleotide sequence of one clone (pS2B1) was identical to that of pS2 cDNA previously reported except for one nucleotide in the 3' untranslated region. The other clone (pS2B2) was longer by 73 nucleotides, at the 5' end, than pS2B1. The additional 73 nucleotides are located just upstream of the sequence of pS2B1 in the structure of the pS2 gene, indicating that the pS2 gene has two start sites for transcription. However, a mRNA molecule corresponding to pS2B1 but not to pS2B2 was detected in the cells on RNA blot hybridization analysis, indicating that one transcriptional start site is mainly used.
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PMID:Complete primary structure of the human estrogen-responsive gene (pS2) product. 218 38

We have examined the synthesis of the protease inhibitors alpha 1-antitrypsin (alpha 1-AT) and alpha 1-antichymotrypsin (alpha 1-ACHY) by variants of the MCF-7 human breast cancer cell line. Spent medium from MCF-7 203P cells, grown in the absence of serum, was found to contain immunoreactive alpha 1-AT and alpha 1-ACHY by Western blotting. In the presence of 10(-8) M estradiol, levels of both inhibitors were increased 3- to 6-fold. Incubation of spent medium with [125I]trypsin or [125I]chymotrypsin resulted in the formation of stable 75- and 90-kDa complexes identical to the complexes formed between these proteases and the protease inhibitors in plasma, showing the release of active protease inhibitors by MCF-7 cells in culture. Immunoprecipitation of 35S-labeled proteins from the medium of cells grown in the presence of [35S]methionine yielded comparable results, confirming hormonally sensitive synthesis of both protease inhibitors. Northern blot analysis suggests that stimulation of estradiol occurs at the level of transcription. Tetradecanoyl phorbol acetate (50 ng/ml) also stimulated alpha 1-AT and alpha 1-ACHY synthesis 2- to 4-fold, suggesting the involvement of protein kinase-C. Comparison studies with MCF-7 cell sublines ML, BK, 203P, and 300P (a variant spontaneously appearing after 100 passages of 203P) show a wide variation in synthesis of alpha 1-AT and alpha 1-ACHY proteins; sublines 203P and 300P synthesize both inhibitors, the ML subline synthesizes detectable amounts only of alpha 1-ACHY, while no detectable synthesis of either inhibitor was seen in the BK subline. Similar results were obtained for protease inhibitor mRNA transcription by Northern blotting, although low levels of alpha 1-AT mRNA transcription by the ML subline and of alpha 1-AT and alpha 1-ACHY mRNA transcription by the BK subline could be detected.
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PMID:Regulation of antitrypsin and antichymotrypsin synthesis by MCF-7 breast cancer cell sublines. 220 35

A 71-yr-old woman with a widely metastatic lipid-rich variant of breast cancer was found to have striking hyperamylasemia (85-fold normal). By isoelectric focusing, agarose gel electrophoresis, and a wheat protein inhibitor assay, the predominant serum amylase appeared to be identical to pancreatic isoamylase. Serum trypsin, serum lipase, and an abdominal computed tomography scan were normal, excluding the possibility of pancreatitis. Furthermore, both the primary breast tumor and skin metastases that developed 10 yr later stained immunohistochemically for amylase. Thus, breast carcinoma must be added to the list of tumors causing ectopic hyperamylasemia, and this case shows that nonpancreatic malignancies may produce pancreatic-type hyperamylasemia.
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PMID:A unique case of breast carcinoma producing pancreatic-type isoamylase. 244 52


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