title: Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression.
abstract: The heparan sulfate proteoglycan syndecan-1 (Sdc1) modulates cell proliferation, adhesion, migration and angiogenesis. Proteinase-mediated shedding converts Sdc1 from a membrane-bound coreceptor into a soluble effector capable of binding the same ligands. In breast carcinomas, Sdc1 overexpression correlates with poor prognosis and an aggressive phenotype. To distinguish between the roles of membrane-bound and shed forms of Sdc1 in breast cancer progression, human MCF-7 breast cancer cells were stably transfected with plasmids overexpressing wild-type (WT), constitutively shed and uncleavable forms of Sdc1. Overexpression of WT Sdc1 increased cell proliferation, whereas overexpression of constitutively shed Sdc1 decreased proliferation. Fibroblast growth factor-2-mediated mitogen-activated protein kinase signaling was reduced following small-interfering RNA (siRNA)-mediated knockdown of Sdc1 expression. Constitutively, membrane-bound Sdc1 inhibited invasiveness, whereas soluble Sdc1 promoted invasion of MCF-7 cells into matrigel matrices. The latter effect was reversed by the matrix metalloproteinase inhibitors N-isobutyl-N-(4-methoxyphenylsufonyl) glycyl hydroxamic acid and tissue inhibitor of metalloproteinase (TIMP)-1. Affymetrix microarray analysis identified TIMP-1, Furin and urokinase-type plasminogen activator receptor as genes differentially regulated in soluble Sdc1-overexpressing cells. Endogenous TIMP-1 expression was reduced in cells overexpressing soluble Sdc1 and increased in those overexpressing the constitutively membrane-bound Sdc1. Moreover, E-cadherin protein expression was downregulated in cells overexpressing soluble Sdc1. Our results suggest that the soluble and membrane-bound forms of Sdc1 play different roles at different stages of breast cancer progression. Proteolytic conversion of Sdc1 from a membrane-bound into a soluble molecule marks a switch from a proliferative to an invasive phenotype, with implications for breast cancer diagnostics and potential glycosaminoglycan-based therapies.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Münster, Münster, Germany.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Nikolova
authors.forename: Chuay-Yeng
authors.initials: CY
authors.lastname: Koo
authors.forename: Sherif Abdelaziz
authors.initials: SA
authors.lastname: Ibrahim
authors.forename: Zihua
authors.initials: Z
authors.lastname: Wang
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.forename: Rita
authors.initials: R
authors.lastname: Dreier
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kelsch
authors.forename: Jeanett
authors.initials: J
authors.lastname: Fischgräbe
authors.forename: Martin
authors.initials: M
authors.lastname: Smollich
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rossi
authors.forename: Walter
authors.initials: W
authors.lastname: Sibrowski
authors.forename: Pia
authors.initials: P
authors.lastname: Wülfing
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kiesel
authors.forename: George W
authors.initials: GW
authors.lastname: Yip
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D009154:Mutation; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D013449:Sulfonamides / Q000494:pharmacology; D053668:Syndecan-1 / Q000235:genetics / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; C500716:N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid; D013449:Sulfonamides; D053668:Syndecan-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D016222:Fibroblast Growth Factor 2