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)

The antiestrogen tamoxifen is used in the treatment of hormone-responsive breast cancer. However, therapeutic failure has frequently been observed in both patients and animal models after long term treatment. We have studied the effect of a point mutation that leads to the substitution of Val for Gly at codon 400 in the ligand-binding domain of the estrogen receptor (ER) on estrogenic and antiestrogenic activities of 4-hydroxytamoxifen (4-OHT) and its derivatives. Stable ER transfectants derived from MDA-MB-231 CL10A, an ER-negative breast cancer cell line, have been used in these studies. 4-OHT and its fixed ring derivatives showed more estrogen-like activity in ER transfectants than in MCF-7, an ER-positive breast cancer cell line. In this study, 4-OHT was a partial agonist of cell growth in the transfectant S30 cells, which express the wild-type ER. However, it was a full agonist in the mutant ER transfectant ML alpha 2H, which expressed ER with Val at codon 400. The increased estrogenic activity of 4-OHT in ML alpha 2H cells was not due to the preferential isomerization of trans 4-OHT to cis 4-OHT, since the nonisomerizable fixed ring trans 4-OHT was a partial agonist for cell growth in S30 cells and was a full agonist in ML alpha 2H cells. Transient transfection using a reporter plasmid containing an estrogen response element demonstrated that fixed ring trans 4-OHT had estrogenic activity in ML alpha 2H cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Point mutation of estrogen receptor (ER) in the ligand-binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing complementary DNAs for ER. 149 96

The antiproliferative effect of two LH-RH agonists (Pro 9-LH-RH ethylamide and D Ser(t BU)6 Aza Gly 10-LH-RH, ICI 118630) on the human breast cancer cell line CG5 is reported. Although ineffective when used alone, both analogs inhibited in a dose-dependent fashion the growth stimulatory effect of estradiol. LH-RH analogs did not influence the growth inhibitory effect of tamoxifen and medroxyprogesterone acetate. Likewise, these compounds neither modified basal estrogen and progesterone receptor levels nor prevented estrogen-induced increase of progesterone receptor. A marked antiproliferative effect of the analogs was also seen in cells stimulated with other mitogens, such as insulin and epidermal growth factor.
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PMID:Growth inhibitory effect of LH-RH analogs on human breast cancer cells. 296 64

This paper first reports the results of 12 patients with sex hormone-dependent neoplasms, including 9 women with breast cancer, 2 men with osteosarcoma and 1 man with prostate carcinoma, treated by LRH agonist, (D-Ala6, des-Gly-NH2(10))-LRH-ethylamide (LRH-A) 100-200 micrograms, IM, QD. After 15-30 days of administration, the concentrations of plasma mean estradiol, progesterone, testosterone, serum luteinizing hormone and follicle-stimulating hormone were lowered significantly in the peripheral blood of all patients, associating with improvement of the patients' general condition and reduction of the tumors and/or metastatic foci. No serious side effects were observed except vaginal irregular bleeding in isolated patients. Three patients died and the others were alive in follow-up of 4-30 months. The results suggest that LRH-A be useful in the treatment of the sex hormone-dependent tumors and worth further study.
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PMID:[Luteinizing hormone-releasing hormone (LRH) agonist in the treatment of breast cancer, osteosarcoma and prostate carcinoma--analysis of 12 patients]. 304 77

The oestrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding and activation of transcription. We show here that the human ER gene is greater than 140 kb in length, split into eight exons and that the positions of these introns have been highly conserved when compared with the chicken progesterone receptor and are remarkably similar to those of one of the chicken thyroid hormone receptor genes. The N-terminal A/B region, which is not conserved between the different members of the nuclear receptor family, is almost entirely encoded within a single exon. Notably each of the putative 'zinc fingers' of the receptor DNA-binding domain is encoded separately, and the hormone-binding domain is assembled from five exons. In addition, we find that the ER isolated from the human breast cancer cell line MCF-7 contains a Gly-400----Val mutation present in the hormone-binding domain.
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PMID:Genomic organization of the human oestrogen receptor gene. 314 93

One hundred thirty-two patients with breast cancer were examined for exposure of cryptantigens on their erythrocytes (RBC) using a lectin panel consisting of Arachis hypogaea and Glycine soja. Eight had exposed cryptantigens; of the eight, five were classified with additional lectins as T-polyagglutination type and three as Th-polyagglutination. A control group of 300 healthy blood donors had no exposed cryptantigens on their RBC. These findings could not be correlated with the staging of the tumor, extension of metastases, or positive estrogen or progesterone receptors of malignant tumor cells. Only one study has been found that describes the incidence of agglutination of erythrocytes from cancer patients using a monoclonal antibody, which detected an epitope on the RBC from cancer patients and was considered to be distinct from the antigen bound by naturally occurring anti-T. Studies have been made describing polyagglutinable sites on breast cancer tumor cells, where there was a much higher incidence. This discrepancy can be explained either by a difference in the methods used to search for cryptantigen exposure on the various types of cells, or by the existence of a different mechanism, which causes the exposure of cryptantigens on RBC as opposed to malignant breast tumor cells.
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PMID:Exposure of cryptantigens on erythrocytes in patients with breast cancer. 336 68

New approaches to the therapy for some endocrine-dependent tumors with analogs of hypothalamic hormones are being developed on the basis of experimental studies in animal models. Analogs of luteinizing hormone-releasing hormones (LH-RH) may open new vistas for the treatment of some hormone-dependent carcinomas. It has been clearly demonstrated that both agonistic and antagonistic analogs of LH-RH can inhibit the growth of rat prostate tumors. A successful treatment of androgen-dependent prostate cancer with agonistic analogs of D-Trp6-LH-RH, D-Ser(But)6des-Gly-NH2(10)-LH-RH ethylamide, and D-Leu6-des-Gly-NH2(10)-LH-RH ethylamide has been documented in several hundred patients. The data accumulated so far from clinical trials suggest that LH-RH agonists can be used as an effective endocrine therapy for prostate carcinoma, therapy avoiding the side effects of estrogen and the psychologic impact of castration. Experimental animal studies and some clinical trials suggest that LH-RH agonists and/or antagonists might also be useful in the treatment of breast cancer. The results of experiments with various hypothalamic analogs in animal models of chondrosarcomas, osteosarcomas, and other tumors appear to be encouraging, but the potential clinical efficacy of LH-RH analogs in the treatment of human hormone-sensitive cancers other than breast and prostate remains to be investigated. The approach to treatment of hormone-dependent tumors based on analogs of hypothalamic hormones might become a useful addition to conventional methods for cancer therapy.
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PMID:Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms. 636 68

We have found that the gamma-carboxyglutamic acid (GLA)-containing protein from bone (BGP, osteocalcin) has chemotactic activity in vitro for a number of cells which are found adjacent to endosteal bone surfaces in vivo. Using the Boyden chamber technique for measuring cell chemotaxis in vitro, we have shown that BGP is chemotactic for cultured human breast cancer cells, human and mouse monocytes, and for cultured rat osteosarcoma cells which have the characteristics of osteoblasts. The migration of these cells in response to BGP is undirectional and not due to spontaneous or random migration. A synthetic peptide (Phe-Tyr-Gly-Pro-Val), which is identical to the carboxy-terminal peptide cleaved from BGP when digested by trypsin, is also chemotactic for the same cells. BGP retains its chemotactic activity after conversion of the gamma-carboxyglutamic acid residues to glutamic acid, indicating that this biological effect requires neither gamma-carboxyglutamate nor the ability of BGP to bind calcium. Since BGP is released from bone during states of increased bone turnover, it is possible that this chemotactic effect of the protein may be a mechanism for recruitment of these cells to sites of active bone remodeling.
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PMID:Chemotactic activity of the gamma-carboxyglutamic acid containing protein in bone. 660 77

Single-chain Fv fusions with C-terminal cysteinyl peptides (sFv') have been engineered using model sFv proteins based upon the 26-10 anti-digoxin IgG and 741F8 anti-c-erbB-2 IgG monoclonal antibodies. As part of the 741F8 sFv construction process, the PCR-amplified 741F8 VH gene was modified in an effort to correct possible primer-induced errors. Genetic replacement of the N-terminal beta-strand sequence of 741F8 VH with that from the FR1 of anti-c-erbB-2 520C9 VH resulted in a dramatic improvement of sFv folding yields. Folding in urea-glutathione redox buffers produced active sFv' with a protected C-terminal sulfhydryl, presumably as the mixed disulfide with glutathione. Disulfide-bonded (sFv')2 homodimers were made by disulfide interchange or oxidation after reductive elimination of the blocking group. Both 26-10 (sFv')2 and 741F8 (sFv')2 existed as stable dimers that were well behaved in solution, whereas 741F8 sFv and sFv' exhibited considerable self-association. The 741F8 sFv binds to the extracellular domain (ECD) of the c-erbB-2 oncogene protein, which is often overexpressed in breast cancer and other adenocarcinomas. The recombinant ECD was prepared to facilitate the analysis of 741F8 binding site properties; the cloned ECD gene, modified to encode a C-terminal Ser-Gly-His6 peptide, was transfected into Chinese hamster ovary cells using a vector that also expressed dihydrofolate reductase to facilitate methotrexate amplification. Optimized cell lines expressed ECD-His6 at high levels in a cell bioreactor; after isolation by immobilized metal affinity chromatography, final ECD yields were as high as 47 mg/l. An animal tumor model complemented physicochemical studies of 741F8 species and indicated increased tumor localization of the targeted 741F8 (sFv')2 over other monovalent 741F8 species.
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PMID:Engineering disulfide-linked single-chain Fv dimers [(sFv')2] with improved solution and targeting properties: anti-digoxin 26-10 (sFv')2 and anti-c-erbB-2 741F8 (sFv')2 made by protein folding and bonded through C-terminal cysteinyl peptides. 747 92

mAb BW835 (IgG1) has been generated to breast cancer cell lines by alternating injections of MCF-7 or SW-613 cells and has been demonstrated to be of value in the serodiagnosis of mammary carcinoma. BW835 defines a carbohydrate epitope on integrated or secreted MUC1 glycoforms from carcinoma cells and human milk. To identify BW835-reactive glycopeptides on MUC1, proteolytic fragments of the mucin obtained by digestion with the Gly-C-specific endopeptidase IV from papaya corresponding to low molecular mass fragments (< 10 kilodaltons) of the tandem repeat domain were screened. A glycosylated fragment (glycopeptide 17) containing the mAb HMFG-2-defined epitope was highly reactive to BW835 antibody, while nonglycosylated tandem repeat peptide TAP25 or its in vitro-glycosylated N-acetylgalactosamine (GalNAc) derivatives were unreactive. Glycopeptide 17 bound to peanut agglutinin and to a Thomsen-Friedenreich antigen (TF alpha)-specific mAb (A78-G/A7). Binding of BW835 to glycopeptide 17 or to MUC1 was competitively inhibited by peanut agglutinin and by the synthetic glycopeptides TF alpha Ser or TF alpha Thr but not by their beta-anomers. Evidence for site specificity of binding by BW835 to glycopeptide 17 was revealed by demonstrating nonreactivity of the antibody to other TF alpha-expressing glycoproteins with peptide moieties lacking MUC1-specific motifs at putative glycosylation sites. The epitope of BW835 was localized to threonine within the VTSA-peptide motif by site-specific enzymatic beta-galactosylation of the synthetic tandem repeat peptide TAP25-GalNAc1 TAPPAHGVT(-O-alpha GalNAc)SAPDTRPAPGSTAPPA. This is the first report on a TF alpha-specific mAb that shows a strict peptide sequence dependency of binding.
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PMID:Monoclonal antibody BW835 defines a site-specific Thomsen-Friedenreich disaccharide linked to threonine within the VTSA motif of MUC1 tandem repeats. 754 84

Evidence indicates that a component of the multicatalytic proteinase complex (MPC) that preferentially cleaves bonds after branched chain amino acids (BrAAP) is a major factor responsible for the protein-degrading activity of the MPC. We report here the synthesis of substrate-related peptidyl aldehydes that inhibit the activity of this component toward both synthetic peptide substrates and proteins. The most potent of the inhibitors, Cbz-Gly-Pro-Phe-leucinal (Cbz-GPFL-CHO) inhibits competitively with a Ki of 1.5 microM. The peptidyl aldehydes also inhibit the small neutral amino acid preferring and the peptidylglutamyl-peptide hydrolyzing activities of the MPC. The chymotrypsin-like activity is only weakly inhibited, and the trypsin-like activity is moderately activated. The importance of a Pro residue in the P3 position and a leucinal residue in the P1 position for inhibition of the BrAAP component is indicated by the finding that replacement of these residues by a glycine or phenylalaninal, respectively, markedly increases the Ki. Cbz-GPFL-CHO inhibited the BrAAP activity with the same Ki both before and after activation of this component by exposure of the MPC to 3,4-dichloroisocoumarin, suggesting that the peptidyl aldehyde is an effective inhibitor of both the overt and latent proteolytic activities of the MPC. Incubation of a human breast cancer cell line (MCF-7) in culture with the inhibitors of the BrAAP component led to an accumulation of ubiquitin-protein conjugates, indicating inhibition of the ubiquitin-dependent proteolytic pathway.
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PMID:Inhibition of the proteolytic activity of the multicatalytic proteinase complex (proteasome) by substrate-related peptidyl aldehydes. 796 80


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