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)

This study examines the Helix pomatia lectin (HPA) binding characteristics of metastases arising from primary breast cancer, and compares HPA binding patterns with binding of Dolichos biflorus lectin (DBA), Limax flavus lectin (LFA), and a monoclonal antibody against the Tn epitope. Of 81 blocks of metastases in a range of tissues, taken at autopsy from 46 individuals, 79% were HPA positive. No site specificity with regard to HPA binding was observed. Both HPA-positive and -negative tumour deposits were seen within a single individual. HPA-positive tumours were commonly negative for binding of sialic acid specific lectin LFA (86% were negative). Binding patterns of alpha-GalNAc specific HPA and DBA, and a monoclonal antibody against Tn epitope (GalNAc-O-Ser/Thr) were markedly different.
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PMID:Expression of N-acetyl galactosaminylated and sialylated glycans by metastases arising from primary breast cancer. 1047 24

The lectin from Helix pomatia, the Roman snail (HPA), recognises terminal alpha N-acetylgalactosamine residues. A large number of lectin histochemical studies have demonstrated that expression of HPA-binding glycoproteins by cancer cells to be a marker of metastatic competence and poor prognosis in a range of common human adenocarcinomas, including those of breast, stomach, ovary, oesophagus, colorectum, thyroid and prostate. Around 80% of metastases arising from primary breast cancer are predictably HPA positive, but, intriguingly, around 20% do not express HPA binding glycoproteins reflecting the complexity of metastatic mechanisms and the further disruptions in cellular glycosylation that attend tumour progression. HPA binding is not an independent prognostic factor, but is strongly associated with the presence of metastases in local lymph nodes. It does appear to be independent of other clinical features of prognostic importance such as tumour size, histological grade, S-phase fraction, ploidy, and there is little convincing evidence of any association with oncogene expression or hormone receptor positivity. The precise nature of the metastasis-associated HPA binding partner(s) is a question of some interest, but thus far remains unclear. HPA will recognise, for example, the Tn epitope and blood group A antigen, but its prognostic significance appears to be through recognition of a much broader and heterogeneous array of N-galactosaminylated glycoproteins. Their synthesis appears to be mediated through alteration in expression or activity of one or more of the enzymes of glycosylation. The most likely putative roles of HPA-binding ligands in the metastatic cascade may be enhancement of invasive capacity, or interaction with an as yet unidentified lectin-like receptor facilitating adhesion processes. The prognostic information provided by HPA lectin histochemistry may be used clinically to inform the physician and aid treatment decisions; far more interesting is the challenge of further understanding the precise nature of the HPA-binding ligands, and defining their role in the complex mechanisms of metastasis.
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PMID:The involvement of Helix pomatia lectin (HPA) binding N-acetylgalactosamine glycans in cancer progression. 1066 5

Antibodies (Abs) to MUC1 occur naturally in both healthy subjects and cancer patients and can be induced by MUC1 peptide vaccination. We compared the specificity of natural and induced MUC1 Abs with the objective of defining an effective MUC1 vaccine for active immunotherapy of adenocarcinoma patients. Serum samples, selected out of a screened population of 492 subjects for their high levels of IgG and/or IgM MUC1 Abs, were obtained from 55 control subjects and from 26 breast cancer patients before primary treatment, as well as from 19 breast cancer patients immunized with MUC1 peptides coupled to keyhole limpet hemocyanin (KLH) and mixed with QS-21. The samples were tested with enzyme-linked immunoassays for reactivity with (1) overlapping hepta- and 20-mer peptides spanning the MUC1 tandem repeat sequence; (2) two modified 60-mer peptides with substitutions in the PDTR (PDTA) or in the STAPPA (STAAAA) sequence of each tandem repeat; and (3) four 60-mer glycopeptides with each 1, 2, 3 and 5 mol N-acetylgalactosamine (GalNAc) per repeat. More than one minimal epitopic sequence could be defined, indicating that Abs directed to more than one region of the MUC1 peptide core can coexist in one and the same subject. The most frequent minimal epitopic sequence of natural MUC1 IgG and IgM Abs was RPAPGS, followed by PPAHGVT and PDTRP. MUC1 peptide vaccination induced high titers of IgM and IgG Abs predominantly directed, respectively, to the PDTRPAP and the STAPPAHGV sequences of the tandem repeat. Natural MUC1 Abs from breast cancer patients reacted more strongly with the N-acetylgalactosamine (GalNAc) peptides than with the naked 60-mer peptide, while reactivity with the GalNAc-peptides was significantly reduced (2-tailed p < 0.0001) in the MUC1 IgG and IgM Abs induced by MUC1 peptide vaccination. Whereas in cancer patients glycans appear to participate in epitope conformation, the epitope(s) recognized by MUC1 Abs induced by peptide vaccination are already masked by minimal glycosylation. Therefore, our results indicate that a MUC1 glycopeptide would be a better vaccine than a naked peptide.
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PMID:Reactivity of natural and induced human antibodies to MUC1 mucin with MUC1 peptides and n-acetylgalactosamine (GalNAc) peptides. 1079 94

In breast cancer, the O-glycans added to the MUC1 mucin are core 1- rather than core 2-based. We have analyzed whether competition by the glycosyltransferase, ST3Gal-I, which transfers sialic acid to galactose in the core 1 substrate, is key to this switch in MUC1 glycosylation that results in the expression of the cancer-associated SM3 epitope. Of the three enzymes known to convert core 1 to core 2, by the addition of GlcNAc to GalNAc in core1 C2GnT1 is the dominant enzyme expressed in normal breast tissue. Expression of C2GnT1 is low or absent in around 50% of breast cancers, whereas expression of ST3Gal-I is consistently increased. Mapping of ST3Gal-I and C2GnT1 within the Golgi pathway showed some overlap. To examine functional competition, the enzymes were overexpressed in T47D cells, which normally make core 1-based structures, have no detectable C2GnT1 activity and express the SM3 epitope. Overexpression of C2GnT1 resulted in loss of binding of SM3 to MUC1, accompanied by a decrease in the GalNAc/GlcNAc ratio, indicative of a switch to core 2 structures. Transfection of a C2GnT1 expressing line with ST3Gal-I restored SM3 binding and reduced GlcNAc incorporation into MUC1 O-glycans. Thus, even when C2GnT1 is expressed, the O-glycans added to MUC1 become core 1-dominated structures, provided expression of ST3Gal-I is increased as it is in breast cancer.
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PMID:The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. 1111 34

Binding of the lectin from Helix pomatia (HPA), which recognises N-acetylgalactosamine and N-acetylglucosamine glycans, is a predictor of metastasis and poor prognosis in a number of human adenocarcinomas, including breast cancer. The glycoproteins to which it binds in these tumours have been only partially characterised, and the mechanisms underlying their biosynthesis remain unknown. In this study, 111 primary breast cancers were assessed for binding of HPA and labelling characteristics were compared directly with those of Dolichos biflorus agglutinin and soybean agglutinin, both of which also recognise N-acetylgalactosamine, Griffonia simplicifolia agglutinin II, which recognises N-acetylglucosamine, and Limax flavus agglutinin, Sambucus nigra agglutinin and Maackia amurensis lectin I, all of which recognise sialic acids. Results indicate that the HPA-binding partners expressed by cancer cells are predominantly N-acetylgalactosamine glycans, but some recognition of N-acetylglucosamine species is also likely. There was no evidence to support the hypothesis that overexpression of these moieties results from failure in sialylation. Alternative mechanisms, for example alterations in levels of activity of appropriate glycosyl transferases or disruption in transport and processing mechanisms leading to failure of normal chain extension of glycans may be responsible, and these are areas that warrant further investigation.
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PMID:N-acetylgalactosamine, N-acetylglucosamine and sialic acid expression in primary breast cancers. 1125 26

Novel glycodendrimers based on N,N'-bis(acrylamido)acetic acid core with valencies between two and six were synthesized. The breast cancer-associated T-antigen carbohydrate marker, (beta-Gal-(1-3)-alpha-GalNAc-OR), was then conjugated by (i) 1,4-conjugate addition of thiolated T-antigen to the N-acrylamido dendritic cores and by (ii) amide bond formation between an acid derivative of the T-antigen and the polyamino dendrimers. The protein-binding ability of these new glycodendrimers was fully demonstrated by turbidimetric analysis and by enzyme-linked immunosorbent assay (ELISA) using peanut lectin from Arachis hypogaea and a mouse monoclonal antibody (MAb) FAA-J11 (IgG3). When tested as inhibitors of binding between MAb and a polymeric form of the T-antigen (T-antigen-co-polyacrylamide) used as a coating antigen, di- (17), tetra- (20), hexa- (21), and tetravalent (22) dendrimers showed IC(50) values of 174, 19, 48, and 18 nM, respectively. Two tetramers showed 120- to approximately 128-fold increased inhibitory properties over the monovalent antigen 6 used as a standard (IC(50) 2.3 mM). Heterobifunctional glycodendrimer bearing a biotin probe was also prepared for cancer cell labeling.
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PMID:Synthesis of N,N'-bis(acrylamido)acetic acid-based T-antigen glycodendrimers and their mouse monoclonal IgG antibody binding properties. 1145 98

Over-expression of N-acetylgalactosamine glycoproteins as detected by binding of the lectin from Helix pomatia (HPA), is associated with metastatic competence and poor patient prognosis in a range of human adenocarcinomas. These glycoproteins remain poorly characterised, and their functional role has yet to be elucidated. This study describes characterisation of a range of human breast/breast cancer cell lines for the expression of the N-acetylgalactosaminylated glycoproteins of interest, and their comparison with normal breast epithelium and a range of clinical breast carcinoma samples. Confocal and light microscopy studies revealed cytochemical HPA-binding patterns consistent with a fundamental disruption in normal glycobiosynthetic pathways attending increasing metastatic potential. We report the most complete comparative analysis of HPA-binding ligands from cultured breast cells, clinical breast carcinoma samples and normal breast epithelium to date. Lectin blotting identified 11 major HPA-binding glycoprotein bands common to both clinical tumour samples and breast cell lines and 6 of these bands were also expressed by samples of normal breast epithelium, albeit at much lower levels. Moreover, very marked quantitative but not qualitative differences in levels of expression consistent with metastatic capability were noted.
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PMID:GalNAc glycoprotein expression by breast cell lines, primary breast cancer and normal breast epithelial membrane. 1159 74

Sialyl-Tn (STn) is a carbohydrate antigen formed by the premature 2-6 sialylation of N-acetylgalactosamine. It belongs to a family of antigens widely expressed in carcinomas but only to a limited degree in normal tissue. The expression of STn has been associated with prognosis in different tumors. In this immunohistochemical study of 218 patients with invasive stage I-III breast cancer, STn was expressed in 39% of the tumors. High expression of STn correlated with estrogen and progesterone hormone receptor negativity (p = 0.0002 and p = 0.0003, respectively), and marginally with large tumor size (p = 0.04), high S-phase fraction (p = 0.04) and aneuploidy (p = 0.04), but not significantly with node status, grade or age. The patients had a median follow-up of 17 years. The breast-cancer-specific survival rate of patients with STn-negative cancers was higher than that of patients with cancers that expressed STn during the first 5 years of the follow-up (p = 0.013), but the difference between the groups decreased during the long-term follow-up. STn expression seems to be a marker for short-term, but not for long-term breast cancer outcome prediction.
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PMID:STn and prognosis in breast cancer. 1172 Nov 77

Mucin glycoproteins on breast cancer cells carry shortened carbohydrate chains. These partially deglycosylated mucin 1 (MUC-1) structures are recognized by the monoclonal antibody SM3, which is being tested for its diagnostic utility. We used NMR spectroscopy to analyze the binding mode and the binding epitope of peptide and glycopeptide antigens to the SM3 antibody. The pentapeptide PDTRP and the glycopentapeptide PDT(O-alpha-D-GalNAc)RP are known ligands of the monoclonal antibody. The 3D structures of the ligands in the bound conformation were determined by analyzing trNOESY build-up rates. The peptide was found to adopt an extended conformation that fits into the binding pocket of the antibody. The binding epitopes of the ligands were determined by saturation transfer difference (STD) NMR spectroscopy. The peptide's epitope is predominantly located in the N-terminal PDT segment whereas the C-terminal RP segment has fewer interactions with the protein. In contrast, the glycopeptide is interacting with SM3 utilizing all its amino acids. Pro1 shows the strongest binding effect that slightly decays towards Pro5. The GalNAc residue interacts mainly via the N-acetyl residue while the other protons show less interactions similar to that of Pro5. The glycopeptide in the bound state also has an extended conformation of the peptide with the carbohydrate oriented towards the N-terminus. Docking studies showed that peptide and glycopeptide fit the binding pocket of the mAb SM3 very well.
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PMID:NMR-based determination of the binding epitope and conformational analysis of MUC-1 glycopeptides and peptides bound to the breast cancer-selective monoclonal antibody SM3. 1187 59

Glycodendrimers are relatively novel synthetic biomacromolecules that are made of biologically relevant carbohydrate ligands constructed at the periphery of a wide range of highly functionalized and repetitive scaffolds having varied molecular weights and structures. They were aimed to fill the gap between glycopolymers, having generally dispersed higher molecular weight, and small glycoclusters, in the study of multivalent carbohydrate protein interactions. In a way, glycodendrimers, with their spheroidal or dendritic (wedge) type structures, were initially designed as bioisosteres of cell surface multiantennary glycans. Taken as a curiosity and elegant molecules at their beginning, they are now considered as potent inhibitors of microbial adhesins. They have also been shown to play some roles in signal transduction and in receptor cross-linking. This brief report will describe advances that have been made toward the syntheses of a range of glycodendrimers bearing the immunodominant T-antigen disaccharide [beta-D-Gal-(1-3)-alpha-D-GalNAc] found on malignant cells of carcinomas, particularly related to breast cancer. This antigen, usually cryptic on healthy tissues, is greatly increased on cancer cells as a result of aberrant glycosylation. It is considered to be an important cancer marker. The high incidence of these carcinomas to invade other tissues such as lymph nodes, lung, and liver by metastasis was one of the arguments raised to generate T-antigen dendrimers that might have the potential to block the receptor sites following surgery. The synthesis of the T-antigen disaccharide will be briefly described, followed by the elaboration of neoglycoproteins and glycopolymers used to raise monoclonal antibodies against the T-antigen and for screening purpose, respectively. Scaffolds made of poly(amidoamine) (PAMAM), poly(propylene imine), N,N'-bis(acrylamido)acetic acid, and finally hyperbranched L-lysine were used to construct relatively small glycodendrimers bearing T-antigen moieties. Few glycodendrimers were also linked to fluorescein and biotin probes to generate ligands that can be used to detect T-Ag receptor sites.
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PMID:Glycodendrimers: novel glycotope isosteres unmasking sugar coding. case study with T-antigen markers from breast cancer MUC1 glycoprotein. 1207 Dec 30


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