title: Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer.
abstract: Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with > or = 10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc(+) breast cancer cells under basal and transforming growth factor-beta (TGF-beta)-stimulated conditions. In addition, exogenous addition of BMP7 to TGF-beta-stimulated MDA-231 cells inhibited Smad-mediated TGF-beta signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 mug/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc(+) cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer.
authors: Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands. J.T.Buijs@lumc.nl
authors: Jeroen T
authors: JT
authors: Buijs
authors: Nico V
authors: NV
authors: Henriquez
authors: Petra G M
authors: PG
authors: van Overveld
authors: Geertje
authors: G
authors: van der Horst
authors: Ivo
authors: I
authors: Que
authors: Ruth
authors: R
authors: Schwaninger
authors: Cyrill
authors: C
authors: Rentsch
authors: Peter
authors: P
authors: Ten Dijke
authors: Anne-Marie
authors: AM
authors: Cleton-Jansen
authors: Keltouma
authors: K
authors: Driouch
authors: Rosette
authors: R
authors: Lidereau
authors: Richard
authors: R
authors: Bachelier
authors: Slobodan
authors: S
authors: Vukicevic
authors: Philippe
authors: P
authors: Clézardin
authors: Socrates E
authors: SE
authors: Papapoulos
authors: Marco G
authors: MG
authors: Cecchini
authors: Clemens W G M
authors: CW
authors: Löwik
authors: Gabri
authors: G
authors: van der Pluijm
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta