Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers.
The glycome acts as an essential interface between cells and the surrounding microenvironment. However, changes in glycosylation occur in nearly all breast cancers, which can alter this interaction. Here, we report that profiles of glycosylation vary between ER-positive and ER-negative breast cancers. We found that genes involved in the synthesis of sialyl-Lewis x (sLe(x); FUT3, FUT4, and ST3GAL6) are significantly increased in estrogen receptor alpha-negative (ER-negative) tumors compared with ER-positive ones. SLe(x) expression had no influence on the survival of patients whether they had ER-negative or ER-positive tumors. However, high expression of sLe(x) in ER-positive tumors was correlated with metastasis to the bone where sLe(x) receptor E-selectin is constitutively expressed. The ER-positive ZR-75-1 and the ER-negative BT20 cell lines both express sLe(x) but only ZR-75-1 cells could adhere to activated endothelial cells under dynamic flow conditions in a sLe(x) and E-selectin-dependent manner. Moreover, L/P-selectins bound strongly to ER-negative MDA-MB-231 and BT-20 cell lines in a heparan sulfate (HS)-dependent manner that was independent of sLe(x) expression. Expression of glycosylation genes involved in heparan biosynthesis (EXT1 and HS3ST1) was increased in ER-negative tumors. Taken together, our results suggest that the context of sLe(x) expression is important in determining its functional significance and that selectins may promote metastasis in breast cancer through protein-associated sLe(x) and HS glycosaminoglycans.
Breast Cancer Biology, King's College London, Guy's Hospital, London, United Kingdom.
Sylvain
S
Julien
Aleksandar
A
Ivetic
Anita
A
Grigoriadis
Ding
D
QiZe
Brian
B
Burford
Daisy
D
Sproviero
Gianfranco
G
Picco
Cheryl
C
Gillett
Suzanne L
SL
Papp
Lana
L
Schaffer
Andrew
A
Tutt
Joyce
J
Taylor-Papadimitriou
Sarah E
SE
Pinder
Joy M
JM
Burchell
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D054794:Glycomics / Q000379:methods; D006497:Heparan Sulfate / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016256:Lewis X Antigen / Q000235:genetics / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000080506:Sialyl Lewis X Antigen; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; D000099058:Exostosin 1
D019040:E-Selectin; D005647:Fucosyltransferases; D006497:Heparan Sulfate; D016256:Lewis X Antigen; D017351:N-Acetylglucosaminyltransferases; D011960:Receptors, Estrogen; D000080506:Sialyl Lewis X Antigen; D012799:Sialyltransferases; D015238:Sulfotransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; D000099058:Exostosin 1; C066693:FUT4 protein, human; C019818:3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase; C021350:heparitin sulfotransferase; C000722087:ST3GAL1 protein, human