Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients

Antonio Russo, Cinzia Ortega, Francesco Pantano, Nicla La Verde, Camillo Porta, Alessandro Ruggiero, Grazia Armento, Isabelle Treilleux, Andrea Onetti Muda, Philippe Clezardin, Giuseppe Perrone, Laura Gaeta, Gaia Schiavon, Nicla La Verde, Cinzia Caroti, Sara Galluzzo, Raffaele Addeo, Bruno Vincenzi, Giuseppe Tonini, Daniele Santini

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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. Materials and 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.
Lingua originaleEnglish
Numero di pagine0
RivistaPLoS One
Volume6
Stato di pubblicazionePublished - 2011

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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Russo, A., Ortega, C., Pantano, F., La Verde, N., Porta, C., Ruggiero, A., Armento, G., Treilleux, I., Muda, A. O., Clezardin, P., Perrone, G., Gaeta, L., Schiavon, G., La Verde, N., Caroti, C., Galluzzo, S., Addeo, R., Vincenzi, B., Tonini, G., & Santini, D. (2011). Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients. PLoS One, 6.