title: HS3ST2 modulates breast cancer cell invasiveness via MAP kinase- and Tcf4 (Tcf7l2)-dependent regulation of protease and cadherin expression.
abstract: Heparan sulfate 3-O-sulfotransferase 2 (HS3ST2), an enzyme mediating 3-O-sulfation of heparan sulfate (HS), is silenced by hypermethylation in breast cancer. As HS has an important co-receptor function for numerous signal transduction pathways, the phenotypical changes due to HS3ST2 reexpression were investigated in vitro using high and low invasive breast cancer cell lines. Compared to controls, highly invasive HS3ST2-expressing MDA-MB-231 cells showed enhanced Matrigel invasiveness, transendothelial migration and motility. Affymetrix screening and confirmatory real-time PCR and Western blotting analysis revealed increased expression of several matrix metalloproteinases, cadherin-11, E-cadherin and CEACAM-1, while protease inhibitor and annexin A10 expression were decreased. Low invasive HS3ST2 -expressing MCF-7 cells became even less invasive, with no change in gelatinolytic MMP activity. HS3ST2 expression increased HS-dependent basal and FGF2-specific signaling through the constitutively active p44/42 MAPK pathway in MDA-MB-231 cells. Increased MAPK activation was accompanied by upregulation of ß-catenin in MDA-MB-231, and of the transcription factor Tcf4 in both cell lines. Dysregulation of Tcf4-regulated ion transporters and increased cytosolic acidification were observed in HS3ST2-expressing MDA-MB-231 cells, which is a possible underlying cause of increased chemosensitivity towards doxorubicine and paclitaxel in these cells. This study provides the first in vitro evidence of the involvement of HS3ST2 in breast cancer cell invasion and chemosensitivity.
authors.affiliation: Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
authors.forename: Archana
authors.initials: A
authors.lastname: Vijaya Kumar
authors.forename: Ezeddin
authors.initials: E
authors.lastname: Salem Gassar
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.forename: Christian
authors.initials: C
authors.lastname: Stock
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Sen
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Toin H
authors.initials: TH
authors.lastname: Van Kuppevelt
authors.forename: Carolin
authors.initials: C
authors.lastname: Hülsewig
authors.forename: Eliene O
authors.initials: EO
authors.lastname: Koszlowski
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavao
authors.forename: Sherif A
authors.initials: SA
authors.lastname: Ibrahim
authors.forename: Michaela
authors.initials: M
authors.lastname: Poeter
authors.forename: Ursula
authors.initials: U
authors.lastname: Rescher
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kiesel
authors.forename: Suresh
authors.initials: S
authors.lastname: Koduru
authors.forename: George W
authors.initials: GW
authors.lastname: Yip
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D006025:Glycosaminoglycans; D012333:RNA, Messenger; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D020928:Mitogen-Activated Protein Kinases; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase
keywords: cadherin; chemosensitivity; glycosaminoglycan; heparan sulfate; invasiveness; metastasis; signal transduction