title: Targeting syndecan-1 in breast cancer inhibits osteoclast functions through up-regulation of osteoprotegerin.
abstract: BACKGROUND
  Breast cancer often metastasizes into bone and leads to osteolytic lesions. The underlying mechanisms, however, are complex and not fully understood. Syndecan-1 is a proteoglycan that has various functions relevant for tumor progression including cell-cell communication and cell-matrix interactions. Moreover, its two glycosaminoglycan-binding sites suggest that it may interfere with glycoproteins such as osteoprotegerin, a potent inhibitor of osteoclastogenesis. Thus, we hypothesize that tumor-derived syndecan-1 alters osteoclast biology by modulating osteoprotegerin.
  
  
  METHODS
  Syndecan-1 expression was down-regulated via siRNA and the cell fate of the breast cancer cell lines MCF-7, T-47D, and MDA-MB-231 was investigated. Furthermore, we determined the regulation of syndecan-1 by dexamethasone, a commonly used antiemetic in breast cancer therapy. Additionally, we analyzed the genesis and activity of osteoclasts in indirect co-culture experiments using supernatants from MCF-7 cells with deficient and sufficient levels of syndecan-1.
  
  
  RESULTS
  Dexamethasone time- and dose-dependently increased syndecan-1 expression up to 4-fold but did not alter cell behavior. Syndecan-1 up-regulation did not affect the survival or migration of breast cancer cells. Depletion of syndecan-1 using siRNA led to decreased vitality of progesterone receptor-positive cell lines. In MCF-7 cells osteoprotegerin production was up-regulated 2.5-fold after syndecan-1 knock-down. The culture of osteoclast precursors with the supernatant of MCF-7 cells with reduced syndecan-1 levels suppressed osteoclast formation and activity by 21% and 23%, respectively. Adding neutralizing antibodies to osteoprotegerin to the breast cancer supernatants reversed osteoclastogenesis.
  
  
  CONCLUSIONS
  Thus, we identified tumor-derived syndecan-1 as a novel positive regulator of osteoclastogenesis and new player in the tumor-bone dialog.
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Benad-Mehner
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Göbel
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany; Center for Regenerative Therapies Dresden, Technical University, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
keywords: ACTB, β-actin; Breast cancer; C, control; DEX, dexamethasone; ER, estrogen receptor; ERBB2, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; GAPDH, glyceraldehyde 3-phosphate-dehydrogenase; OPG, osteoprotegerin; Osteoclast; Osteoprotegerin; PR, progesterone receptor; RANKL, receptor activator of NF-κB ligand; SDC1, syndecan-1; Syndecan-1