Over-expression of ST3Gal-I promotes mammary tumorigenesis.
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 (Galbeta1,3GalNAc) 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.
Departments of Medicine and Biochemistry, Queen's University, Ontario, Canada.
Gianfranco
G
Picco
Sylvain
S
Julien
Inka
I
Brockhausen
Richard
R
Beatson
Aristotelis
A
Antonopoulos
Stuart
S
Haslam
Ulla
U
Mandel
Anne
A
Dell
Sarah
S
Pinder
Joyce
J
Taylor-Papadimitriou
Joy
J
Burchell
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D015153:Blotting, Western; D005260:Female; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D047468:Immunoprecipitation; D007774:Lactation / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000235:genetics; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D000952:Antigens, Polyomavirus Transforming; D018396:Mucin-1; D012333:RNA, Messenger; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D005690:Galactose; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase