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)

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

The alpha 1-antitrypsin (AAT) or protease inhibitor (Pi) genetic polymorphism was studied in 144 white, 100 coloured, 104 Indian and 127 black (Northern Sotho) healthy individuals (controls), in the Pretoria area. Their Pi phenotype and gene frequency distributions are compared with world-wide data on other population groups. The severely deficient Pi phenotypes S, Z and SZ jointly attain frequencies of 0.3-0.4% in coloureds and whites; in blacks and Indians the corresponding frequencies are very much lower. The implication for preventive medicine and public health is that in South Africa the sequelae of Pi deficiencies such as cirrhosis of the liver and/or emphysema of the lung are of practical importance in whites and coloureds and much less so in blacks and Indians. In 176 white breast cancer patients studied, the Pi phenotype and gene frequency distributions were found to be similar to those of healthy controls (not statistically significant). Cohorts of other patients were also phenotyped because of their low alpha 1-globulin concentrations in routine serum protein electrophoresis and/or their specific disease condition (cirrhosis of the liver or emphysema of the lung) known to be associated with AAT deficiency. These results are discussed in terms of their significance for family follow-up, genetic counselling and a preventive service. The need to avoid atmospheric pollution, especially cigarette smoke, is emphasised as a major and cost-effective preventive measure.
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PMID:Alpha-1-antitrypsin genetic polymorphism in South Africa. 349 69

Two human breast cancer cell lines (T-47D and MCF-7) and one cell line derived from normal human milk (HBL-100) not only specifically bound but also degraded prolactin. Quantitative differences in the ability to bind and degrade prolactin among the cell lines exist, although there was a good correlation between the number of prolactin receptor sites and prolactin degradative activity. Iodo-prolactin as well as native prolactin were degraded. The prolactin molecule was processed to yield at least three small molecular weight peptides which were released into the incubation medium. These peptides neither bound to fresh receptors nor to anti-prolactin antibodies. The protease inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone, lysosomotropic agents such as chloroquine and ammonium chloride, and metabolic inhibitors 2,4-dinitrophenol and sodium azide, all abolished prolactin degradation by the breast cancer cells. When prolactin degradation was inhibited, specific binding and the subsequent release of intact 125I-prolactin was still observable, suggesting that hormonal degradation was not a prerequisite to dissociation of prolactin. However, prolactin degradation did account for the accelerated rate of dissociation of prolactin. Studies utilizing inhibitors suggest that the receptor-bound 125I-prolactin was degraded by an energy-dependent internalization process such as pinocytosis; lysosomal enzymes are probably involved in the degradation of prolactin by human breast cancer cells.
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PMID:Processing of prolactin by human breast cancer cells in long term tissue culture. 624 18

Vertical tube rotor sucrose gradient centrifugation in the presence of the protease inhibitor sodium molybdate provide to give a deeper insight into the steroid hormone receptor status of human malignant melanoma (MM) as did previous studies using dextran-coated charcoal procedure only. As compared to endocrine dependent breast cancer, the oestrogen binding capacity of MM is low. Although in some biopsies fairly high concentrations of progestin binders were detected, the sedimentation properties were not receptor typic. Androgen binding was found to be negligible. In contrast, the presence of glucocorticoid receptors is a common feature of human MM. A human MM cell line was demonstrated to contain glucocorticoid receptors only.
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PMID:Gradient centrifugation analysis of steroid-hormone binding in human malignant melanoma. 714 55

Alpha 1-antichymotrypsin, a serum protease inhibitor, was found in 72 breast cyst fluids aspirated from women affected by gross cystic breast disease. When fractionated by gel chromatography, the presence of protein complexes or aggregates was demonstrated. A different distribution of the alpha 1-antichymotrypsin appeared to be related to the ionic composition of the breast cyst fluid; when compared with metabolically active apocrine cysts, a statistically significant increase of alpha 1 protease inhibitor values in flattened epithelial cysts was revealed (P < 0.001). Two-dimensional immunoelectrophoresis showed in apocrine cysts (Na/K ratio < 3) a characteristic double peak of alpha 1-antichymotrypsin immunoprecipitin curve. The relationship between this alpha 1 protease inhibitor and electrolyte profiles may provide further knowledge about the imbalance between proteases and their inhibitors on functional changes of gross cysts and might be useful in studies on their mechanism of formation and relationship to subsequent breast cancer.
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PMID:Alpha 1-antichymotrypsin complexes in human breast cyst fluids. 814 44

Topical drug delivery is important from the view points of improvement of therapeutic effect and reduction of systemic side effects. Utilization of polymeric materials seemed to be as a key for the development of new topical dosage forms including targeting drug delivery systems. Adriamycin ointment for local chemotherapy to breast cancer prepared using polyethylene glycol, ammonium polyacrylate and hydroxypropyl cellulose (HPC) according to an optimum formulation showed an excellent clinical effect in spite of a decreased drug content. Double-layered mucoadhesive sticks for the treatment of uterine cervix cancer were prepared by direct compression of powder mixture of bleomycin, HPC and carboxyvinyl polymer (CP). Drug release property of the sticks could be controlled by the weight of outer layer, drug combining ratio to each layer and coating of core layer. The results suggested a possibility of a "once-a-week" treatment that is preferable for the patients. Magnetic granules for the treatment of esophageal cancer were prepared using ferrite, HPC and CP. Magnetic guidance and retainment of the granules on esophageal mucosa were confirmed using rabbits in vivo. Buoyant sustained release preparations were prepared using chitosan, soybean protein, HPC and other polymers. Usefulness of the buoyant preparations was suggested from the results in vitro and in vivo. Insulin microspheres (IMS) for targeting delivery to the small intestine were prepared by the newly developed method. Employment of enteric coating material (Eudragit) and combination of protease inhibitor protected insulin from enzymatic attack and gave decreased levels of blood glucose by oral administration.
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PMID:[Development of topical drug delivery systems utilizing polymeric materials]. 833 78

alpha 1-Antitrypsin (alpha 1-AT) and alpha 1-antichymotrypsin (alpha 1-ACHY) are closely related protease inhibitors, synthesized primarily by the liver, which play major roles in modulation of the inflammatory response. Previously, we had shown that MCF-7 human breast cancer cells were able to synthesize active alpha 1-AT and alpha 1-ACHY and that the synthesis of both inhibitors varied among different MCF-7 sublines. We now show that when MCF-7(ML) cells (a subline synthesizing low levels of alpha 1-AT) are grown in soft agar in medium depleted of its trypsin inhibitory capacity (i.e. alpha 1-AT-free), addition of alpha 1-AT (50 micrograms/ml) significantly reduces colony formation in both the presence and absence of estradiol (34% and 44%, respectively). Under these conditions, incubation with 10(-7) M estradiol alone increased colony formation 2- to 3-fold. Colony formation was also significantly reduced by serum leukocyte protease inhibitor, which, like alpha 1-AT, is a potent inhibitor of elastase-like enzymes. We also found that a variety of inflammatory mediators, cytokines, and steroid hormones are able to stimulate synthesis of alpha 1-AT and alpha 1-ACHY by MCF-7 cells. Stimulation by interleukin-6 (IL-6; 200 U/ml), epidermal growth factor (4 nM), and estradiol (10(-7) M) was 2- to 3-fold, whereas stimulations by tetradecanoylphorbol-13-acetate (TPA; 80 nM) and IL-1 (10 U/ml) were 2- to 5-fold and 5- to 10-fold, respectively. In each instance, protein synthesis, monitored by immunoprecipitation of 35S-labeled proteins followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and steady state mRNA levels, monitored by Northern blot analysis with specific cDNA probes, increased to the same extent. Consistent with their ability to stimulate alpha 1-AT synthesis, TPA and IL-1 reduced colony formation in the absence of estradiol by 65% and 63%, respectively. In addition, the effects of both TPA and IL-1 could be reversed by antibody to alpha 1-AT. These results suggest that local synthesis of alpha 1-AT and possibly other protease inhibitors may be important in regulating the tumorigenic potential of MCF-7 breast cancer cells.
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PMID:alpha 1-Antitrypsin- and anchorage-independent growth of MCF-7 breast cancer cells. 836 78

A trypsin-chymotrypsin inhibitor was isolated from the seeds of amaranth--a highly nutritious protein source. The purification of the inhibitor (AmI) was carried out by affinity chromatography on trypsin-Sepharose and by HPLC. AmI is a single-chain protein of 8 kD, as determined by electrophoresis on SDS-polyacrylamide gels and by gel exclusion on Sephadex G-50 column. It is stable at neutral and alkaline pH and is relatively thermostable. AmI inhibits trypsin and chymotrypsin from the digestive system of insects such as Tribolium castaneum and Locusta migratoria, supporting the hypothesis that inhibitors may have evolved as defense mechanisms of seeds against insects. AmI lost its inhibitory activities when submitted to limited proteolysis with trypsin, while limited proteolysis with chymotrypsin had almost no effect. The partial amino acid sequence of 45 amino acids from the amino terminus of AmI differs significantly from the known sequences of legume-seed and cereal-grain protease inhibitor families. Differences in the chemistry at the inhibitory site(s) and in the amino acid sequence of AmI in comparison to that of other cereal and legume inhibitors suggest that AmI is a member of a new family of serine protease inhibitors. AmI was found to inhibit the anchorage-independent growth of MCF-7 breast cancer cells, suggesting that AmI may have anticarcinogenic activity.
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PMID:Isolation, characterization, and properties of a trypsin-chymotrypsin inhibitor from amaranth seeds. 892 6

The purpose of this study was to determine whether inhibition of lysosomal proteolysis could be used to selectively inhibit proliferation of tumor cells. The lysosomal cysteine protease inhibitor 9-fluorenylmethyloxycarbonyl-tyrosylalanyl-diazomethane was found to inhibit growth of the breast cancer cell lines SK-Br-3 and MCF-7. A humanized monoclonal antibody (huMAb 4D5) directed against the extracellular domain of p185HER2 specifically inhibited growth of the SK-Br-3 cells, which overexpress this antigen. The antibody and inhibitor together showed enhanced inhibition of growth of the SK-Br-3 cells only. When the protease inhibitor was radiolabeled and conjugated to the antibody (huMAb 4D5-125I-Tyr-Ala-CHN2) it was selectively bound to and taken up by the SK-Br-3 cell line. The conjugated inhibitor was delivered and targeted to cathepsin B and an unidentified protein of Mr 39,000 in the SK-Br-3 cells. Internalization of huMAb 4D5-125I-Tyr-Ala-CHN2 and inhibitor labeling of the proteins were temperature-dependent processes. huMAb 4D5-Tyr-Ala-CHN2 was significantly more effective in inhibiting proliferation of SK-Br-3 cells than the inhibitor-free analogue but was ineffective against MCF-7 cells. The results in this report show that targeting of cysteine protease inhibitors can selectively control tumor cell growth and that targeted cysteine protease inhibitors could prove valuable in the development of novel anticancer immunotherapies.
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PMID:Control of breast tumor cell growth using a targeted cysteine protease inhibitor. 950 Apr 48

We have reported the tumor suppressive effects of manganese-containing superoxide dismutase (MnSOD) in human breast cancer cells. In order to understand the molecular mechanism of this anti-tumor effect, we asked whether tumor suppressor gene(s), especially the ones inhibiting tumor invasion and motility, are involved in MnSOD-induced tumor suppression. Maspin is one of the serpin family of protease inhibitors that has been shown to function as a tumor-suppressor in human breast epithelium. In the present study, we demonstrated that maspin expression was up-regulated in human breast cancer MCF-7 cells that overexpress a normal MnSOD gene. The induced maspin transcripts were detected by RT-PCR and Northern blot and identified by sequencing. Maspin gene expression was induced in parallel with the level of exogenous MnSOD protein, which was induced by transfection with varied amounts of cDNA. In order to analyze cell invasion ability, which may be related to the induced maspin gene expression, MnSOD stable transfectants were tested using a matrigel invasion chamber. The invasion ability was reduced to 24% and 36% in the cloned (MCF + SOD) and pooled MnSOD-transfectants (MCF + SODp) respectively, compared with the wild-type MCF-7 cell line. In conclusion, these results suggest that overexpression of a normal MnSOD cDNA in human breast cancer cells up-regulates the gene expression of the protease inhibitor, maspin, which may play a role in the inhibitory function of MnSOD on tumor invasion.
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PMID:Maspin gene expression in tumor suppression induced by overexpressing manganese-containing superoxide dismutase cDNA in human breast cancer cells. 963 71


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