title: Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients.
abstract: BACKGROUND
  Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG.
  
  
  METHODS
  We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival.
  
  
  RESULTS
  Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that "RANK-negative" and "RANK-positive" patients had a SDFS of 105.7 months (95% CI: 73.9-124.4) and 58.9 months (95% CI: 34.7-68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029).
  
  
  CONCLUSIONS
  This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients.
authors.affiliation: Department of Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy. d.santini@unicampus.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Laura
authors.initials: L
authors.lastname: Gaeta
authors.forename: Francesco
authors.initials: F
authors.lastname: Pantano
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ortega
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Sara
authors.initials: S
authors.lastname: Galluzzo
authors.forename: Grazia
authors.initials: G
authors.lastname: Armento
authors.forename: Nicla
authors.initials: N
authors.lastname: La Verde
authors.forename: Cinzia
authors.initials: C
authors.lastname: Caroti
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ruggiero
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Addeo
authors.forename: Philippe
authors.initials: P
authors.lastname: Clezardin
authors.forename: Andrea Onetti
authors.initials: AO
authors.lastname: Muda
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
mesh_terms: D000368:Aged; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D053244:Osteoprotegerin / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis*
chemical_list: D008024:Ligands; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human