Over-expression of ST3Gal-I promotes mammary tumorigenesis

TY - JOUR

T1 - Over-expression of ST3Gal-I promotes mammary tumorigenesis

AU - Picco, Gianfranco

AU - Julien, Sylvain

AU - Brockhausen, Inka

AU - Beatson, Richard

AU - Antonopoulos, Aristotelis

AU - Haslam, Stuart

AU - Mandel, Ulla

AU - Dell, Anne

AU - Pinder, Sarah

AU - Taylor-Papadimitriou, Joyce

AU - Burchell, Joy

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Changes in glycosylation are common in malignancy, and as almost all surface proteins are glycosylated, this can dramatically affect the behavior of tumor cells. In breast carcinomas, the O-linked glycans are frequently truncated, often as a result of premature sialylation. The sialyltransferase ST3Gal-I adds sialic acid to the galactose residue of core 1 (Galβ1,3GalNAc) O-glycans and this enzyme is over-expressed in breast cancer resulting in the expression of sialylated core 1 glycans. In order to study the role of ST3Gal-I in mammary tumor development, we developed transgenic mice that over-express the sialyltransferase under the control of the human membrane-bound mucin 1 promoter. These mice were then crossed with PyMT mice that spontaneously develop mammary tumors. As expected, ST3Gal-I transgenic mice showed increased activity and expression of the enzyme in the pregnant and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background. These results indicate that ST3Gal-I is acting as a tumor promoter in this model of breast cancer. This, we believe, is the first demonstration that over-expression of a glycosyltransferase involved in mucin-type O-linked glycosylation can promote tumorigenesis.

AB - Changes in glycosylation are common in malignancy, and as almost all surface proteins are glycosylated, this can dramatically affect the behavior of tumor cells. In breast carcinomas, the O-linked glycans are frequently truncated, often as a result of premature sialylation. The sialyltransferase ST3Gal-I adds sialic acid to the galactose residue of core 1 (Galβ1,3GalNAc) O-glycans and this enzyme is over-expressed in breast cancer resulting in the expression of sialylated core 1 glycans. In order to study the role of ST3Gal-I in mammary tumor development, we developed transgenic mice that over-express the sialyltransferase under the control of the human membrane-bound mucin 1 promoter. These mice were then crossed with PyMT mice that spontaneously develop mammary tumors. As expected, ST3Gal-I transgenic mice showed increased activity and expression of the enzyme in the pregnant and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background. These results indicate that ST3Gal-I is acting as a tumor promoter in this model of breast cancer. This, we believe, is the first demonstration that over-expression of a glycosyltransferase involved in mucin-type O-linked glycosylation can promote tumorigenesis.

KW - Animals

KW - Antigens, Polyomavirus Transforming

KW - Blotting, Western

KW - Female

KW - Galactose

KW - Glycosylation

KW - Humans

KW - Immunoprecipitation

KW - Lactation

KW - Mammary Glands, Animal

KW - Mammary Neoplasms, Experimental

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Mucin-1

KW - N-Acetylneuraminic Acid

KW - Pregnancy

KW - Promoter Regions, Genetic

KW - RNA, Messenger

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Sialyltransferases

U2 - 10.1093/glycob/cwq085

DO - 10.1093/glycob/cwq085

M3 - Journal article

C2 - 20534593

SN - 0959-6658

VL - 20

SP - 1241

EP - 1250

JO - Glycobiology

JF - Glycobiology

IS - 10

ER -