Receptor activator of NF-kB (rank) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere19234
JournalPLoS One
Volume6
Issue number4
DOIs
Publication statusPublished - 2011

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Osteoprotegerin
transcription factor NF-kappa B
NF-kappa B
RANK Ligand
metastasis
breast neoplasms
Tumors
Bone
bones
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
receptors
neoplasms
Disease-Free Survival
Neoplasms
Microarrays
Messenger RNA
Survival
Bone Remodeling

ASJC Scopus subject areas

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

Cite this

Receptor activator of NF-kB (rank) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. / Santini, Daniele; Schiavon, Gaia; Vincenzi, Bruno; Gaeta, Laura; Pantano, Francesco; Russo, Antonio; Ortega, Cinzia; Porta, Camillo; Galluzzo, Sara; Armento, Grazia; La Verde, Nicla; Caroti, Cinzia; Treilleux, Isabelle; Ruggiero, Alessandro; Perrone, Giuseppe; Addeo, Raffaele; Clezardin, Philippe; Muda, Andrea Onetti; Tonini, Giuseppe.

In: PLoS One, Vol. 6, No. 4, e19234, 2011.

Research output: Contribution to journalArticle

Santini, D, Schiavon, G, Vincenzi, B, Gaeta, L, Pantano, F, Russo, A, Ortega, C, Porta, C, Galluzzo, S, Armento, G, La Verde, N, Caroti, C, Treilleux, I, Ruggiero, A, Perrone, G, Addeo, R, Clezardin, P, Muda, AO & Tonini, G 2011, 'Receptor activator of NF-kB (rank) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients', PLoS One, vol. 6, no. 4, e19234. https://doi.org/10.1371/journal.pone.0019234
Santini, Daniele ; Schiavon, Gaia ; Vincenzi, Bruno ; Gaeta, Laura ; Pantano, Francesco ; Russo, Antonio ; Ortega, Cinzia ; Porta, Camillo ; Galluzzo, Sara ; Armento, Grazia ; La Verde, Nicla ; Caroti, Cinzia ; Treilleux, Isabelle ; Ruggiero, Alessandro ; Perrone, Giuseppe ; Addeo, Raffaele ; Clezardin, Philippe ; Muda, Andrea Onetti ; Tonini, Giuseppe. / Receptor activator of NF-kB (rank) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. In: PLoS One. 2011 ; Vol. 6, No. 4.
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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.",
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T1 - Receptor activator of NF-kB (rank) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients

AU - Santini, Daniele

AU - Schiavon, Gaia

AU - Vincenzi, Bruno

AU - Gaeta, Laura

AU - Pantano, Francesco

AU - Russo, Antonio

AU - Ortega, Cinzia

AU - Porta, Camillo

AU - Galluzzo, Sara

AU - Armento, Grazia

AU - La Verde, Nicla

AU - Caroti, Cinzia

AU - Treilleux, Isabelle

AU - Ruggiero, Alessandro

AU - Perrone, Giuseppe

AU - Addeo, Raffaele

AU - Clezardin, Philippe

AU - Muda, Andrea Onetti

AU - Tonini, Giuseppe

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0019234

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