title: BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression.
abstract: BACKGROUND
  The transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells.
  
  
  METHODS
  In this study, we investigated the effect of BMP-7 on TGF-β-induced invasion in a 3 dimensional invasion assay.
  
  
  RESULTS
  BMP-7 inhibited TGF-β-induced invasion of the metastatic breast cancer cell line MCF10CA1a, but not of its premalignant precursor MCF10AT in a spheroid invasion model. The inhibitory effect appears to be specific for BMP-7, as its closest homolog, BMP-6, did not alter the invasion of MCF10CA1a spheroids. To elucidate the mechanism by which BMP-7 inhibits TGF-β-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-β-induced expression of integrin α(v)β(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin β(3) negatively affected TGF-β-induced invasion. On the other hand, overexpression of integrin β(3) counteracted the inhibitory effect of BMP7 on TGF-β-induced invasion.
  
  
  CONCLUSIONS
  Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-β-induced expression of integrin β(3).
authors.affiliation: Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hildegonda P H
authors.initials: HP
authors.lastname: Naber
authors.forename: Eliza
authors.initials: E
authors.lastname: Wiercinska
authors.forename: Evangelia
authors.initials: E
authors.lastname: Pardali
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Ella
authors.initials: E
authors.lastname: Nirmala
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.forename: Bertrand
authors.initials: B
authors.lastname: Heckmann
authors.forename: Erik H J
authors.initials: EH
authors.lastname: Danen
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000099176:Noggin Protein
chemical_list: D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D039482:Integrin alpha5; D039661:Integrin beta3; D020778:Matrix Metalloproteinase 2; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C061248:ITGB3 protein, human