title: Role of RANK, RANKL, OPG, and CXCR4 tissue markers in predicting bone metastases in breast cancer patients.
abstract: This is a retrospective study on 40 breast cancer patients, of which 20 have bone metastases, 10 have visceral metastases, and 10 have no evidence of disease, aimed at evaluating the role of CXCR4 and the RANK/RANKL/OPG system to predict bone metastases. CXCR4 expression, alone or in combination with RANK, identified patients destined to relapse to bone.
  
  
  BACKGROUND
  The RANK/RANKL/OPG system is active in primary cancers such as breast, prostate, and also in their bone metastases. CXCR4 chemokine receptor is highly expressed in human breast cancer cells and is believed to facilitate the homing of tumor cells to organs such as bone that express high levels of its ligand SDF1. Our study aimed to investigate whether the analysis of these markers with an inexpensive and simple test can help to predict bone metastases in breast cancer patients.
  
  
  METHODS
  Marker expression was evaluated by immunohistochemical staining in paraffin-embedded tissue sections of primary breast cancers from 40 individuals: 20 patients with bone metastases (BM), 10 with visceral metastases (VM; considered together as the relapsed group), and 10 with no evidence of disease (NED).
  
  
  RESULTS
  RANKL was not detected in tumor cells. OPG- and RANK-positive tumors are found with similar frequency in NED (20%) and in relapsed patients (23% and 17%, respectively). However, in the latter subgroup, only RANK positivity was always associated with bone relapse. The frequency of CXCR4-positive tumors was three-fold higher in relapsed (30%) than in NED (10%) patients and positivity was always linked to bone metastases. Considering NED and VM patients together versus BM patients, we observed that CXCR4 expression, alone (P = .008) or in combination with RANK (P < .001), identified patients destined to relapse to bone.
  
  
  CONCLUSIONS
  Our results provide the first clinical evidence to support a pivotal role of combined CXCR4 and RANK expression in predicting bone relapse.
authors.affiliation: Osteoncology Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy. t.ibrahim@irst.emr.it
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sacanna
authors.forename: Michele
authors.initials: M
authors.lastname: Gaudio
authors.forename: Laura
authors.initials: L
authors.lastname: Mercatali
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Serra
authors.forename: Rossana
authors.initials: R
authors.lastname: Ricci
authors.forename: Luigi
authors.initials: L
authors.lastname: Serra
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin / Q000378:metabolism; D011237:Predictive Value of Tests; D053245:RANK Ligand / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; D053245:RANK Ligand; D019718:Receptors, CXCR4