title: Transforming growth factor-beta signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation.
abstract: Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor-bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-beta receptor 1 (TGF-betaRI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-betaRI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-beta activity by neutralizing antibody to TGF-beta or TGF-betaRI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-betaRI expression and its activation. In addition, we demonstrate a potential role of TGF-beta as an important modifier of receptor activator of NF-kappaB ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-betaRI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5845, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Nannuru
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.forename: Anguraj
authors.initials: A
authors.lastname: Sadanandam
authors.forename: Kimihisa
authors.initials: K
authors.lastname: Nakao
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Sato
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010014:Osteolysis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics; D053245:RANK Ligand / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D053245:RANK Ligand; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I