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 characterized a new tumor-associated antigen defined by monoclonal antibody (MAb) generated against HMA-1 breast cancer cell line. MAb AM-1 was selected based on its preferential reactivity to breast cancer cells versus to normal or benign epithelial cells by immunofluorescence and immunohistochemical assays of cultured, or fresh specimens. AM-1 demonstrated strong reactivity to breast cancer cell lines including HMA-1, YMB-1-E, YMB-1 and MDA-MB-231 in flow cytometry. In immunoprecipitation, AM-1 recognized high molecular weight components of 160-210 kDa and > 370 kDa. Reactivity with HMA-1 cells was diminished markedly when treated by heat, protease or periodate, suggesting that the antigenic epitope is composed with carbohydrates and peptides. Enzyme digestion of precipitated antigens demonstrated that the antigen contains O-linked and N-linked carbohydrates with neuraminic acid structures. Furthermore, binding inhibition and sandwich ELISA assays using MAbs reactive with known breast cancer-associated antigens and synthetic MUC1 core peptide (PDTRPAPGSTAPPAHGVTSAPDTR) demonstrated that the antigen is distinct from CEA, TAG-72 or MUC1, while the antigen conjoins with MUC1 and TAG-72 as a trimmer form in HMA-1 cells. These results suggest that AM-1 recognizes a novel glycoprotein which is abundant in breast cancer, and may be utilized in the management of breast cancer patients.
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PMID:Characterization of a new breast cancer-associated antigen and its relationship to MUC1 and TAG-72 antigens. 905 11

Many chemicals have recently been discovered to have estrogenic activity, including the surfactant intermediate nonylphenol (NP). It has been well documented that estrogen is a facilitator of human breast cancer development under certain conditions, and environmental estrogens such as NP are currently under intense investigation. Using the expression of pS2 (a trefoil peptide expressed in breast cancer cells), MUC1 (a member of the mucin family) and ER (the human estrogen receptor) genes as estrogen-responsive reporter genes, the effects of estradiol and NP on human breast cancer cells-MCF-7 were studied. In the time course study, the mRNA expressions were detected after NP (10 microM) or estradiol (E2, 0.1 microM) treatments using the RT-PCR technique. The results indicated: (1) NP and E2 induced pS2 mRNA expression after a 2-h exposure and (2) NP induction produced the highest level of MUC1 mRNA after 2 h, which was reduced to only 42% of control at 48 h. E2 treatment resulted in a gradual increase in MUC1 expression over the course of the exposure. The highest level of MUC1 mRNA was at 48 h. This indicates that NP may stimulate MUC1 expression by a different mechanism than E2. (3) NP affected ER expression in the same manner as MUC1. In contrast, E2 stimulated ER expression in a similar manner as pS2; the highest level was at 2 h and expression remained elevated through the 48-h point. NP is an estrogenic compound that alters pS2, MUC1 and ER gene expression in MCF-7 cells. NP may affect MUC1 expression through a different mechanism than E2. The link between aberrant MUC1, PS2 and ER expression and the development of breast cancer also needs to be elucidated through further investigation.
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PMID:Estrogenic effects of nonylphenol on pS2, ER and MUC1 gene expression in human breast cancer cells-MCF-7. 915 95

The human MUC1 gene expresses at least 2 type 1 membrane proteins: MUC1/REP, a polymorphic high m.w. MUC1 glycoprotein often highly expressed in breast cancer tissues and containing a variable number of tandem 20 amino acid repeat units, and the MUC1/Y protein, which lacks this repeat array and, therefore, is not polymorphic. Despite their documented importance in signal transduction processes, the relative expression of the 2 isoforms in epithelial tumors is unknown. Using antibody reagents which recognize different MUC1 domains, the expression of these isoforms in malignant epithelial cells has been evaluated. A comparison of the amounts of the 2 isoforms revealed preferential expression of the novel MUC1/Y protein in breast cancer tissue samples. Furthermore, although the MUC1/REP protein is almost undetectable in HeLa cervical adenocarcinoma epithelial cells, the MUC1/Y isoform is extensively expressed in these cells. The presence of the MUC1/Y sequence as well as that of an additional tandem-repeat-array-lacking isoform, designated MUC1/X, were demonstrated by reverse transcriptase PCR amplification of RNA extracted from HeLa and ovarian carcinoma cells. It has been shown previously that the MUC1 cytoplasmic domain interacts with the SH2 domain containing GRB2 protein, which transduces signals to ras, a protein which in its activated form can lead to cell transformation. We present here data demonstrating that MUC1/Y isoform expression increases the tumorigenic potential of DA3 mouse mammary epithelial cells; in contrast, potentiation of tumorigenicity is not observed with MUC1/REP expression. Our studies thus demonstrate that expression of the MUC1 gene in epithelial tumors can give rise to substantial levels of MUC1 proteins devoid of the tandem repeat array, which are generated by alternative splicing mechanisms.
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PMID:Preferential expression of novel MUC1 tumor antigen isoforms in human epithelial tumors and their tumor-potentiating function. 918 Jan 40

The alpha2,3 sialyltransferase, alpha2,3 SAT (O), catalyzes the transfer of sialic acid to Galbeta1,3 N-acetyl-D-galactosamine (GalNAc) (core-1) in mucin type O-glycosylation, and thus terminates chain extension. A Core-2 branch can also be formed from core-1 by the core-2 beta1,6 N-acetyl-d-glucosamine transferase (beta1,6 GlcNAc T) that leads to chain extension. Increased levels of the alpha2,3 SAT (O) and decreased levels of the core-2 beta1,6 GlcNAc T are seen in breast cancer cells and correlate with differences in the structure of the O-glycans synthesized (Brockhausen et al., 1995; Lloyd et al., 1996). Since in mucin type O-glycosylation sugars are added individually and sequentially in the Golgi apparatus, the position of the transferases, as well as their activity, can determine the final structure of the O-glycans synthesized. A cDNA coding for the human alpha2,3 SAT (O) tagged with an immunoreactive epitope from the myc gene has been used to map the position of the glycosyltransferase in nontumorigenic (MTSV1-7) and malignant (T47D) breast epithelial cell lines. Transfectants were analyzed for expression of the enzyme at the level of message and protein, as well as for enzymic activity. In T47D cells, which do not express core-2 beta1,6 GlcNAc T, the increased activity of the sialyltransferase correlated with increased sialylation of core-1 O-glycans on the epithelial mucin MUC1. Furthermore, in MTSV1-7 cells, which do express core-2 beta1,6 GlcNAc T, an increase in sialylated core-1 structures is accompanied by a reduction in the ratio of GlcNAc: GalNAc in the O-glycans attached to MUC1, implying a decrease in branching. Using quantitative immunoelectron microscopy, the sialyltransferase was mapped to the medial- and trans-Golgi cisternae, with some being present in the TGN. The data represent the first fine mapping of a sialyltransferase specifically active in O-glycosylation and demonstrate that the structure of O-glycans synthesized by a cell can be manipulated by transfecting with recombinant glycosyltransferases.
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PMID:A transfected sialyltransferase that is elevated in breast cancer and localizes to the medial/trans-Golgi apparatus inhibits the development of core-2-based O-glycans. 918 58

This study was designed to evaluate the performance of a new automated assay system, the IMMULITE Automated Immunoassay Analyzer in comparison with more commonly used IRMA assays for measuring circulating tumour marker levels in breast cancer patients. The assays investigated measure the MUC1 mucin (CA15-3 antigen) or CEA. Serum samples from breast cancer patients with various stages of disease and from a group of normal individuals were analysed. Significant correlations were found between tumour marker levels measured using the IMMULITE BR-MA and the CA15-3 assays and between levels measured using the two CEA assay formats. Levels of IMMULITE BR-MA and CEA correlated with stage of disease suggesting that both are markers of tumour burden Levels in Stage III breast cancer patients were found to be significantly higher than those of normals using the IMMULITE system but not the IRMA assays. This would suggest a role for the automated system in the monitoring of breast cancer at an earlier stage than that at which tumour markers are routinely used. Elevated marker levels did not correspond to any particular site of metastasis however, a greater proportion of patients with multiple sites of metastasis had elevated levels compared with those with secondary disease at a single site. We conclude that the IMMULITE Automated Immunoassay Analyzer is of value in the routine surveillance of tumour marker levels.
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PMID:Evaluation of the IMMULITE BR-MA and CEA assays and comparison with immunoradiometric assays for CA15-3 and CEA in breast cancer. 921 49

A comparison was made between the murine anti-MUC1 antibody BC2 (which reacts with the peptide epitope APDTR) and the "humanised" antibody hCTMO1 from CellTech, which reacts with the MUC1 epitope RPAP. Preliminary studies demonstrated that hCTMO1 was a "good" antibody whereas BC2 was not. Various parameters were determined and conclusions reached. (a) Affinity: the affinity of hCTMO1 was 2.60 x 10(7) M(-1) and that of BC2 was 1.36 x 10(7) M(-1); we did not consider these numbers to be substantially different, although hCTMO1 was clearly of higher affinity than BC2. (b) On/off rate at 4 degrees C: both antibodies bound effectively to the MUC-1 transfectant MOR5-CF2; the association rate for hCTMO1 was 3.8 times that of BC2 and the dissociation rate for BC2 was twice as fast as that of hCTMO1. (c) On/off rates at 37 degrees C: at 37 degrees C the association rate for hCTMO1 was greater than that of BC2. (d) Internalization: hCTMO1 was also more efficient at internalising bound antibody; 70% of bound hCTMO1 was internalised, whilst 6% of bound BC2 was internalised. From these studies it was clear that, while hCTMO1 was of similar affinity to BC2, the faster uptake and internalisation and lower off rate indicated that it was likely to be a superior antibody; this was proven in vivo. (e) Localisation: hCTMO1 bound much better in vivo than BC2 (68% compared to 28%). (f) Therapeutic experiments: BC2-idarubicin conjugates were essentially ineffective in eradicating tumours in mice whereas hCTMO1-idarubicin had a dramatic effect on breast cancer tumour cells growing in mice. We conclude that the simple measurements on/off rates and internalisation at 37 degrees C are the most important parameters to use to determine antibody effectiveness, prior to embarking on clinical studies.
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PMID:Comparison of the biological properties of two anti-mucin-1 antibodies prepared for imaging and therapy. 929 34

Alterations of the entire long arm of chromosome 1 are the most consistent cytogenetic abnormalities found in human breast carcinoma. Overexpression of a large number of genes, because of acquisition of additional copies of one arm or a whole chromosome, is one possible cause of the imbalance in cell metabolism. To investigate the existence of such a gene dosage effect in breast cancer, we chose to study the MUC1 mucin gene located at 1q21-q24. This gene is highly expressed in breast tumors, but the genetic mechanism for its ectopic overexpression is not clearly known. Thirty-two human primary breast tumors were examined, by Southern blot DNA and northern blot RNA analyses, for allelic dosage and expression of the MUC1 gene. A correlation was found between acquisition of additional copies of MUC1 gene and high mRNA levels (p < 0.0001). These results identify a genetic mechanism responsible for MUC1 gene overexpression and support the hypothesis that a gene dosage effect of the long arm of chromosome 1 may be involved in the pathogenesis of breast cancer.
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PMID:A gene dosage effect is responsible for high overexpression of the MUC1 gene observed in human breast tumors. 930 22

It is demonstrated with glycopeptides of the polymorphic epithelial mucin (MUC1) that post-source decay matrix-assisted laser desorption ionization (PSD-MALDI) is a fast, highly sensitive, and reproducible method for the localization of O-glycosylation sites by reflectron time-of-flight (TOF) mass spectrometry. We have analyzed GalNAc-carrying peptides of up to 25 amino acids, and could distinguish even neighboring glycosylation sites. This method was also able to localize and characterize disaccharides (e.g., the Thomsen-Friedenreich disaccharide) on MUC1 derived peptides. PSD-MALDI-MS fragment ion patterns were recorded in the positive ion mode from the synthetic peptide TAP25 [(T1aAPPAHGVT9S10APDT14RPAPGS20) T1bAPPA], an overlapping sequence of MUC1 tandem repeats, which was glycosylated with GaINAc in vitro. The glycosylation sites found were either Thr9 or Thr1b in the monoglycosylated, Thr9 and Thr1b in the diglycosylated, and Thr9, Thr1b, and Ser20 in the triglycosylated peptide. A single PSD-MALDI-MS spectrum of the underivatized and uncleaved di- or triglycosylated TAP25 peptide was sufficient to identify the glycosylation sites, thereby distinguishing six potential, partly adjacent, glycosylation sites. The monoglycosylated fraction was found to consist of a mixture of two glycosylated species with the same molecular weight. This was shown by the analysis of proteolytic digests. PSD-MALDI-MS of the resulting peptides right out of the digestion probe was sufficient to identify the Gal-NAc-glycosylation sites as either Thr9 or Thr1b, respectively. Beyond the methodical aspects the results revealed that in vitro glycosylation of the TAP25 peptide with a transferase system from human milk differs from that obtained with a breast cancer cell transferase system.
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PMID:A sequencing strategy for the localization of O-glycosylation sites of MUC1 tandem repeats by PSD-MALDI mass spectrometry. 936 30

Alterations in mucin expression have been detected in many clinically relevant cancers and, in particular, the polymorphic epithelial mucin, encoded by the MUC1 gene, has attracted considerable attention. We investigated its expression in human breast, colon, ovarian, lung, and skin cancer cells and their metastases grown in severe combined immunodeficient (scid) mice using three different monoclonal antibodies (HMFG-1, HMFG-2, and SM3). Four of five breast cancer cell lines, three of five colon cancer cell lines, two of three small-cell carcinoma of the lung cell lines, and A 431 cells all expressed the MUC1 gene product. Neuraminidase predigestion often enhanced HMFG-1 immunoreactivity, which was more widespread and stronger than SM3 immunoreactivity. A considerable heterogeneity of MUC1 gene product expression was observed in the same tumors grown in different mice. The binding pattern between single-cell/small-cell clusters (up to 10 cells) and larger cell number aggregates varied. The results indicate that the MUC1 gene expression both in primary tumors and metastases is not tightly controlled within a particular tumor cell line. Because of this heterogeneous antigen expression in vivo, it appears impossible to target all metastatic deposits by a single monoclonal antibody directed against the MUC1 gene product. (J Histochem Cytochem 46:127-134, 1998)
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PMID:Immunohistochemical detection of the MUC1 gene product in human cancers grown in scid mice. 940 2

Paired DNA samples from the neoplastic and nonneoplastic cells of 118 patients with the sporadic, nonfamilial form of breast cancer were analyzed for evidence of genetic alteration at a polymorphic microsatellite mapped to intron 6 within the MUC1 gene at 1q21. Two other microsatellite loci, D1S104 and APO-A2, which also map to 1q21, were analyzed as well. The frequency of alteration at the microsatellite within the MUC1 locus was significantly higher than D1S104 or APO-A2 (P < 0.001). Analysis by Southern blotting of the VNTR region of the MUC1 gene revealed an amplification of one allele in 34 of 54 informative cases (63%). There was no significant association between these alterations and alterations of the microsatellite within the same locus, suggesting independent mechanisms were responsible for the genetic changes. Microsatellite loci D17S579 at 17q21, the site of the BRCA1 gene, and D18S34 at 18q21-qter, the deleted in colorectal cancer locus, were also analyzed by PCR. Alterations at D17S579 and D18S34 were detected in 18.8% and 6.2% of patients, respectively (P < 0.001, and P < 0.1 relative to the frequency of alteration at D1S104 or APO-A2). A previously described polymorphism of hMSH2 was altered in 16.4% of cases.
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PMID:A microsatellite within the MUC1 locus at 1q21 is altered in the neoplastic cells of breast cancer patients. 940 83


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