title: Specific genes involved in synthesis and editing of heparan sulfate proteoglycans show altered expression patterns in breast cancer.
abstract: BACKGROUND
  The expression of a specific set of genes controls the different structures of heparan sulfate proteoglycans (HSPGs), which are involved in the growth, invasion and metastatic properties of cancerous cells. The purpose of this study is to increase knowledge of HSPG alterations in breast cancer.
  
  
  METHODS
  Twenty-three infiltrating ductal adenocarcinomas (IDCs), both metastatic and non-metastatic were studied. A transcriptomic approach to the structure of heparan sulfate (HS) chains was used, employing qPCR to analyze both the expression of the enzymes involved in their biosynthesis and editing, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate chains, we extended the study to include the genes involved in the biosynthesis of these glycosaminoglycans. Histochemical techniques were also used to analyze tissular expression of particular genes showing significant expression differences, of potential interest.
  
  
  RESULTS
  No significant change in transcription was detected in approximately 70% of analyzed genes. However, 13 demonstrated changes in both tumor types (40% showing more intense deregulation in the metastatic), while 5 genes showed changes only in non-metastatic tumors. Changes were related to 3 core proteins: overexpression of syndecan-1 and underexpression of glypican-3 and perlecan. HS synthesis was affected by lower levels of some 3-O-sulfotransferase transcripts, the expression of NDST4 and, only in non metastatic tumors, higher levels of extracellular sulfatases. Furthermore, the expression of chondroitin sulfate also was considerably affected, involving both the synthesis of the saccharidic chains and sulfations at all locations. However, the pro-metastatic enzyme heparanase did not exhibit significant changes in mRNA expression, although in metastatic tumors it appeared related to increased levels of the most stable form of mRNA. Finally, the expression of heparanase 2, which displays anti-metastatic features, experienced a strong deregulation in all patients analyzed.
  
  
  CONCLUSIONS
  IDCs show alterations in the expression of HSPG genes; principally the expression and localization of proteoglycans and the sulfation patterns of glycosaminoglycan chains, depending on the metastatic nature of the tumor. In addition, the anti-proliferative molecule heparanase 2 experiences strong deregulation, thus highlighting it as a potentially interesting diagnostic factor.
authors: Department of Pathology, Hospital Universitario Central de Asturias, Oviedo 33006, Spain.
authors: Iván
authors: I
authors: Fernández-Vega
authors: Olivia
authors: O
authors: García
authors: Ainara
authors: A
authors: Crespo
authors: Sonia
authors: S
authors: Castañón
authors: Primitiva
authors: P
authors: Menéndez
authors: Aurora
authors: A
authors: Astudillo
authors: Luis M
authors: LM
authors: Quirós
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D002809:Chondroitin Sulfates / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics; D053673:Glypicans / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D015238:Sulfotransferases / Q000235:genetics; D053668:Syndecan-1 / Q000235:genetics; D000099175:Heparanase
chemical_list: D014408:Biomarkers, Tumor; D002809:Chondroitin Sulfates; D005966:Glucuronidase; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D012333:RNA, Messenger; D015238:Sulfotransferases; D053668:Syndecan-1; D000099175:Heparanase; C105937:GPC3 protein, human; C508241:SDC1 protein, human; C071927:perlecan; C422953:NDST4 protein, human