Transcriptional regulation of the protocadherin β cluster during Her-2 protein-induced mammary tumorigenesis results from altered N-glycan branching.
Changes in the levels of N-acetylglucosaminyltransferase V (GnT-V) can alter the function of several types of cell surface receptors and adhesion molecules by causing altered N-linked glycan branching. Using a her-2 mammary tumor mouse model, her-2 receptor signaling was down-regulated by GnT-V knock-out, resulting in a significant delay in the onset of her-2-induced mammary tumors. To identify the genes that contributed to this GnT-V regulation of early events in tumorigenesis, microarray analysis was performed using her-2 induced mammary tumors from wild-type and GnT-V-null mice. We found that 142 genes were aberrantly expressed (>2.0-fold) with 64 genes up-regulated and 78 genes down-regulated after deletion of GnT-V. Among differentially expressed genes, the expression of a subgroup of the cadherin superfamily, the protocadherin β (Pcdhβ) cluster, was up-regulated in GnT-V-null tumors. Altered expression of the Pcdhβ cluster in GnT-V-null tumors was not due to changes in promoter methylation; instead, impaired her-2-mediated signaling pathways were implicated at least in part resulting from reduced microRNA-21 expression. Overexpression of Pcdhβ genes inhibited tumor cell growth, decreased the proportion of tumor-initiating cells, and decreased tumor formation in vivo, demonstrating that expression of the Pcdhβ gene cluster can serve as an inhibitor of the transformed phenotype. Our results suggest the up-regulation of the Pcdhβ gene cluster as a mechanism for reduced her-2-mediated tumorigenesis resulting from GnT-V deletion.
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA.
Huabei
H
Guo
Alison
A
Nairn
Mitche
M
dela Rosa
Tamas
T
Nagy
Shaying
S
Zhao
Kelley
K
Moremen
Michael
M
Pierce
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D015820:Cadherins; D035683:MicroRNAs; D017351:N-Acetylglucosaminyltransferases; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse