Glycobiology, 1999, Vol. 9, No. 12 1307-1311
© 1999 Oxford University Press
An 
2,3sialyltransferase (ST3Gal I) is elevated in primary breast carcinomas
Imperial Cancer Research Fund Breast Cancer Biology Groupand 3Hedley Atkins/ICRFBreast Pathology, Guy’s Hospital, London SE1 9RT, UK, 4In situ HybridizationService and Histopathology Unit, Imperial Cancer Research Fund,44 Lincoln’s Inn Fields, London WC2A 3PX, UK, 5Department of Oral Diagnostics,School of Dentistry, University of Copenhagen, DK2200 Copenhagen,Denmark
Received on January 23, 1999. revisedon April 26, 1999; accepted on May 28, 1999.
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Abstract |
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The MUC1 mucin is expressed on the luminal surfaceof most simple epithelial cells but in carcinomas, especially thoseof the breast and ovary, MUC1 is upregulated and aberrantly glycosylated.MUC1 contains a large amount of O-linked glycans which, in the mucinexpressed by normal mammary epithelial cells, consist mainly ofcore 2 based structures carrying polylactosamine chains. However,the mucin expressed by breast carcinomas has shorter side-chains, oftenconsisting of sialylated core 1 (Galß1–3GalNAc). in situ hybridization of primary breasttissue showed that a sialyltransferase (ST3Gal I), responsible foradding sialic acid to core 1 thereby terminating chain extension,is elevated in primary breast carcinomas when compared to normalor benign tissue. Furthermore, the level of mRNA expression encodingST3Gal I is correlated to the intensity of staining seen with theantibody SM3, which specifically recognises underglycosylated, tumourassociated MUC1. Thus, the aberrant glycosylation of MUC1 seen inbreast carcinomas appears to be due, at least in part, to the elevationof ST3Gal I.
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Introduction |
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Changes in the structure of glycan chains attached to glycolipidsand glycoproteins are a common feature of the progression to malignancy(10
Hakomori, 1989). This has aprofound effect on the structure of mucin glycoproteins as theycarry multiple O-linked glycans. The MUC1 mucin is an integral membrane proteinwith a large extracellular domain made up of tandemly repeated aminoacids (8Gendler et al., 1988),the number of which varies with the individual. Each repeat containsfive potential sites for O-linked glycosylation all of which maybe utilised (15Muller et al.,1997). MUC1 is aberrantly glycosylated in 95% ofbreast carcinomas, the side-chains being shorter with a relativelyhigher sialic acid content than those found on the mucin expressedby normal mammary epithelial cells (14Lloyd et al., 1996). This change in O-glycanstructure results in the exposure of peptide epitopes, such as thatrecognised by the monoclonal antibody SM3, which are masked in MUC1 expressedby normal mammary epithelial cells (5Burchell et al., 1987), and in the appearance ofnovel carbohydrate epitopes. This makes the MUC1 expressed by breastcarcinomas antigenically distinct from that expressed by normalmammary cells. Studies with breast cancer cell lines have indicatedthat changes in O-glycan structure correlate with changes in the profileof expression of specific glycosyltransferases (3Brockhausen et al., 1995).
Mucin-type O-linked glycosylation is initiated in the Golgi apparatus(17Rottger et al., 1998)by the addition of N-acetylgalactosamine to the hydroxylgroup of serines and threonines. The oligosaccharide side chainsare then built up by the sequential addition of individual sugars,via various core structures, each reaction being catalyzed by specificglycosyltransferases (2Brockhausen, 1996).Thus the final structure of the O-glycans is determined by the activityof individual glycosyltransferases and by their position relativeto each other in the Golgi pathway.
In the MUC1 mucin, galactose is added to the initial GalNAc toform the core 1 structure, which in normal breast epithelial cellsis then converted to core 2 by the addition of N-acetylglucosamine;the reaction being catalysed by the enzyme core 2 ß1,6N-acetylglucosaminyltransferase (C2GnT). Core 2 is then extendedby the addition of polylactosamine units (11Hanisch et al., 1989; 14Lloyd et al., 1996). However, in breast carcinomas the core1 to core 2 conversion is reduced, resulting in the O-glycans onthe tumour associated MUC1 being shorter and less complex (12Hull et al., 1989; 14Lloyd et al., 1996). ST3GalI, which catalyzes the addition of sialic acid in an 
2,3linkage to Gal ß1–3 GalNAc, terminatingchain extension, uses the same substrate (core 1) as C2GnT. Thus,changes in the expression and activity of these enzymes could leadto changes in the structure and length of the O-glycans attachedto MUC1 and to the exposure of peptide epitopes such as that recognisedby SM3. We have previously shown that, when compared to SM3 negativenormal mammary epithelial cell lines, SM3 positive breast cancercell lines have an 8–10 fold elevation in the enzymic activity responsiblefor transferring sialic acid in 2,3linkage to the core 1 substrate (3Brockhausen et al., 1995). In contrast, C2GnT activityis absent or decreased in the tumor cell lines.
To determine whether similar changes in the expression of glycosyltransferasesare also seen in primary breast cancers we have used insitu hybridization to detect levels of mRNA encoding a specificsialyltransferase, ST3Gal I. Our results show that ST3Gal I mRNAis indeed more abundant in carcinoma than benign breast epitheliumand the level correlates with the intensity of staining with themonoclonal antibody SM3.
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Expression of ST3Gal I and C2GnT transferases bybreast tissues
Expression of mRNA encoding for ST3Gal I or C2GnT was analyzedin 34 breast tissue sections (see Table
).In 22 of the breast carcinoma sections, normal or benign epithelialtissue was observed, and these areas were evaluated separately. ST3GalI expression was detected exclusively in epithelial cells and wasstronger in the carcinomas compared to normal or benign breast tissue(Figure 1). When a scoring system was usedto analyze the intensity of the staining (see Materialsand methods), it became clear that the expression of ST3GalI was elevated in breast carcinomas when compared to normal and benignlesions. Furthermore in ductal carcinomas, the level of expressionappeared to be related to tumor grade (Table ).
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The same breast tissue samples were analyzed by insitu hybridization for C2GnT mRNA expression (see Figure 1). Again C2GnT RNA was mostly observed in theepithelial tissue and, as to be expected from the presence of extendedcore 2 based structure identified on MUC1 isolated from human milk (11
Hanisch et al., 1989),was quite strongly expressed by lactating breast (Figure 1F). However, as can be seen from Table 
, there appears to be no obvious correlationin the expression of this glycosyltransferase with the type of breasttissue.
Elevated level of ST3Gal I is correlated with thestaining intensity of SM3
The monoclonal antibody SM3 was raised to MUC1 largely strippedof its carbohydrate by exposure to hydrogen fluoride (5Burchell et al., 1987). This antibody reacts witha peptide epitope (6Burchell etal., 1989) which is selectively exposed in carcinomas(9Girling et al., 1989).Sections parallel to those used for in situ hybridizationwere stained with SM3 by indirect immunoperoxidase (Figure 1C,G) and the staining intensity scored 0 to +++ withoutknowledge of the ST3Gal I results. Table showsthe staining intensity observed with SM3 in comparison to the levelof expression of ST3Gal I. To analyze if the apparent correlationwas indeed statistically significant, a Spearman’s Correlationtest was performed. This gave a positive correlation with a p valueof 0.0053, indicating that there is a statistically highly significantcorrelation between ST3Gal I mRNA expression and the intensity ofstaining of the monoclonal antibody SM3.
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Increased ST3Gal I mRNA expression is correlatedto increased
2,3 sialic acid structuresIn an attempt to correlate increased ST3GalI mRNA expression withincreased
2,3 oligosaccharides parallelsections of nineteen of the tumors were stained with Maakiaamurensis lectin (Table A) whichrecognizes 2,3 linked sialic acid (13Konami et al., 1994).When these were sections were scored for staining intensity andcompared to ST3Gal I expression a significant positive correlation(p = 0.0015) was found as defined by Spearman’scorrelation test. Furthermore, Maackia amurensis staining was alsostrongly correlated with SM3 epitope expression (p = 0.0001)demonstrating that the staining of this lectin was an indicationof the presence of 2,3 sialic acidon MUC1 (Table B).
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Discussion |
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Although it is well documented that changes in the composition of O-glycansoccur in malignancy (10
Hakomori, 1989),it has rarely been possible to relate these changes with changesin the expression and/or activity of relevant glycosyltransferases (22Yang et al., 1994). Wehave previously shown (3Brockhausen et al., 1995) that, in breast cancer cell lines thetruncated O-glycans carried by the cancer-associated MUC1 mucincorrelates with an increase in sialyltransferase activity responsiblefor the addition of sialic acid in an 2,3linkage to core 1 (Galß1–3GalNAc). Thereare three sialyltransferases, ST3Gal I, ST3Gal II and ST3Gal IVthat could be responsible for this increase in activity (7Chang et al., 1995; 16Recchi et al., 1998),and recently, a PCR method has been developed that can distinguishbetween at least two of these enzymes in cell lines (16Recchi et al., 1998). However, this methodologycannot establish which cell types within a particular specimen express the mRNAs in vivo. We nowshow by in situ hydridization that mRNA encodinga specific sialyltransferase, ST3Gal I, is elevated in primary breastcarcinoma cells compared to normal tissue, and that in ductal carcinomasthe level of mRNA is related to the grade of the tumour. In addition,ST3Gal I mRNA expression was correlated with Maackia amurensis lectinbinding. Although this lectin recognizes 2,3linked sialic acid on O-linked core 1 glycans (13Konami et al., 1994) it is not specific for O-glycans(19Wang and Cummings, 1988). However,its positive correlation with the expression of a peptide epitope(recognized by the monoclonal antibody SM3) on the MUC1 mucin, whichis masked in MUC1 expressed by normal mammary epithelial cells but exposedwhen O-glycan chain extension is inhibited (4Burchelland Taylor-Papadimitriou, 1993), suggests that it is reflecting anincreased in 2,3 sialic acid structureon MUC1. Furthermore, we have previously shown that overexpressionof ST3Gal I does indeed result in the increased sialylation of MUC1 (21Whitehouse et al., 1997).As ST3Gal I expression is also positively correlated with the expressionof the SM3 epitope, the increased expression of ST3Gal I may, atleast in part, explain the truncation of O-glycans carried by thecarcinoma associated mucin which results in the exposure of theSM3 epitope.
In normal breast epithelium, the core 1 glycan is acted uponby C2GnT which initiates chain extension involving the formation of polylactosamineside-chains (11Hanisch et al.,1989; 14Lloyd et al.,1996). Thus, C2GnT could compete with ST3Gal I for thecore 1 substrate. In the cell lines previously examined, the nonmalignant cellline (MTSV1-7) exhibited reasonable levels of the C2GnT, while twoof the three breast cancer lines studied appeared to have lost expressionof this enzyme at the level of the mRNA. In the third cell line,the message level was higher than in the normal cell line but theactivity was lower (3Brockhausen et al., 1995), possibly suggesting posttranscriptionalcontrol. Thus, levels of mRNA encoding C2GnT may not reflect theactivity of the enzyme and indeed, in situ hybridizationof the core 2 transferase mRNA in primary breast cancers showedthere was no consistent pattern of reduction in the level of message expressed.An accurate comparison of glycosyltransferase activity would beextremely difficult to achieve in breast tissue as normal specimensconsist mainly of stroma with very little epithelium, in contrastto tumor samples which can contain a very high proportion of epithelialcells. However, by transfecting ST3Gal I into a cell line expressingactive C2GnT, we have shown that overexpression of ST3Gal I, evenin the presence of active core 2 enzyme, can result in shorter sugarside-chains being found on MUC1 (21Whitehouse et al., 1997). Furthermore, by transfectionof the core 2 enzyme into the breast cancer cell line T47D, we haveshown that the SM3 epitope is masked by the core 2 branch (20Whitehouse, 1998). Thus the positive correlation ofSM3 staining intensity with ST3Gal I expression levels suggeststhat in primary breast carcinomas, overexpression of ST3Gal I allowsthis glycosyltransferase to compete with C2GnT for the core 1 substrate,resulting in sialylation of core 1, inhibiting further chain extension.Monoclonal antibodies to ST3Gal I are now being developed whichwill permit the analysis of the larger number of specimens requiredto confirm the correlation with SM3 binding, and to confirm theassociation of ST3Gal I with increased grade of ductal carcinomas.
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Materials and methods |
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In situ hybridization
Specific localization of the mRNAs for ST3Gal I and human core2 ß1,6 GlcNA was accomplished by insitu hybridization using antisense riboprobes synthesized with 35S-UTP(~800 Ci/mmol; Amersham, UK). Tissue blocks were from thearchives of the Histopathology Unit and Guy’s Hospital.
The template for synthesis of the ST3Gal I riboprobe was SacI linearized pcDNA1 plasmid containing the fullcoding region of human ST3Gal I (7Chang et al., 1995), generously provide by Dr. JosephLau. The riboprobe was produced with Sp6 RNA polymerase and contained942 bases complementary to ST3Gal I mRNA. For human core 2 N-acetylglucosaminyltransferase(C2GnT) (1Bierhuizen and Fukuda, 1992), HaeII linearized pBluescript plasmidcontaining a 1 kb HindIII fragment of C2GnT, obtained by PCR fromthe breast cancer cell line MCF-7, was used with T7 RNA polymeraseto generate a riboprobe containing 965 bases complementary C2GnTtransferase mRNA. Hybridization was essentially as described by 18Senior et al. (1988),for formalin-fixed paraffin-embedded tissue.
The presence of hybridizable mRNA in all compartments of thetissues studied was established in near serial sections using anantisense ß-actin probe generated withSP6 RNA polymerase and DraI linearizedphßA-10, prepared by subcloning a ~450bp region of a human ß-actin cDNA intopSP73.
Autoradiography was at 4°C (twoexposures per section; 11 d and 14 d for the enzyme mRNA targetsand 11d for ß-actin mRNA), before developingin Kodak D19 and counterstaining by Giemsa’s method. Sectionswere examined under conventional or reflected light dark-field conditions(Olympus BH2 with epi-illumination) that allowed individual autoradiographicsilver grains to be seen as bright objects on a dark background.
Evaluation of RNA expression was carried out by assessing the intensityof the silver grains giving a score of 0 for negative, 1+ forweak, 2++ for moderate, and 3+++ forstrong intensity. When a section contained areas of morphologicallydefined malignant and benign tissue, these areas were scored separately.
Histochemistry
Dewaxed and rehydrated 3 µm sectionsfrom the primary tumors of the selected patients were incubatedin tissue culture supernatant containing the mouse monoclonal antibodySM3 for 1 h at room temperature and the binding detected by incubation with aperoxidase conjugated rabbit antimouse and a standard streptavidin–biotincomplex method (DAKO Denmark). Staining was visualized with diaminobenzidine(Sigma UK) and lightly counterstained with hematoxylin. The primaryantibody was omitted and replaced with Tris buffer pH 7.6 on sectionsused as negative controls.
Evaluation of SM3 immunostaining was carried out by assessingthe intensity of apical and cytoplasmic staining, giving a scoreof 0 for negative, 1+ for weak, 2++ formoderate, and 3+++ for strong staining.
The binding of Maackia amurensis was determinedby incubating dewaxed and rehydrated sections with biotinylated Maackia amurensis (Vector Laboratories, UK), followedby streptavidin–biotin horseradish peroxidase. Stainingwas visualized with diaminobenzidine (Sigma UK) and thesections lightly counterstained with hematoxylin. The scoring system wasthe same as that used for SM3. Due to specimen availability, only19 sections were analyzed for Maackia amurensis staining.
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We thank Diana Skilton and Kenneth Ryder for help with the statisticalanalysis and Dr Joe Lau for the kind gift of the ST3Gal I cDNA.We are grateful to Len Rogers, Rosemary Jeffery and Jan Longcroftfor skilled assistance with the in situ hybridizationstudies.
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a Correspondenceto: Dr Joy Burchell, ICRF Breast Cancer Biology Group, 3rd Floor,Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK
b Presentaddress: Cancer Genetics Laboratory, 8th Floor, Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK
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