Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

Fortner, Renée T.; Sarink, Danja; Schöck, Helena; Johnson, Theron; Tjønneland, Anne; Olsen, Anja; Overvad, Kim; Affret, Aurélie; His, Mathilde; Boutron-Ruault, Marie Christine; Boeing, Heiner; Trichopoulou, Antonia; Naska, Androniki; Orfanos, Philippos; Palli, Domenico; Sieri, Sabina; Mattiello, Amalia; Tumino, Rosario; Ricceri, Fulvio; Bueno‐de‐Mesquita, H. Bas; Peeters, Petra H.M.; Gils, Carla H. van; Weiderpass, Elisabete; Lund, Eiliv; Quirós, J. Ramón; Agudo, Antonio; Sánchez, María José; Chirlaque, María Dolores; Ardanáz, Eva; Dorronsoro, Miren; Key, Tim; Khaw, Kay Tee; Rinaldi, Sabina; Dossus, Laure; Gunter, Marc J.; Merritt, Melissa A.; Riboli, Elio; Kaaks, Rudolf

doi:10.1186/s12916-017-0786-8

Cited by 23 publications

(43 citation statements)

References 68 publications

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“…In prostate cancer, increased levels of OPG have been observed in patients with advanced cancer (33,34). In breast cancer, higher concentrations of OPG were associated with an increased risk of ER-negative breast cancer (35). In addition, preclinical studies indicate that OPG mediates tumor-promoting effects as a mediator of inflammation in breast cancer (36) and promotes metastases in triple-negative breast cancer (37).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Rachner

Kasimir‐Bauer

Göbel

et al. 2019

Clinical Cancer Research

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Purpose: We assessed serum concentrations of the receptor activator of NFkB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease.Experimental Design: Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA.Results: RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23-3.07; P ¼ 0.005] and OPG was an independent prognostic marker for breast cancer-specific survival (BCSS; multivariate analyses, P ¼ 0.035). RANKL levels were 33% higher (P < 0.0001) in DTC pos patients (41%), whereas high levels were associated with a significantly better BCSS in DTC neg patients as compared with low levels (HR 0.524; 95% CI 0.30-0.95; P ¼ 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P ¼ 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49-14.34; P ¼ 0.03).Conclusions: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.NOTE: Values of RANKL and OPG are given in pmol/L. RANKL/OPG is displayed as a ratio of the two values. Significant values (P < 0.05) are shown in bold.Rachner et al.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Rachner

Kasimir‐Bauer

Göbel

et al. 2019

Clinical Cancer Research

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“…RANKL signaling also activates downstream signaling cascades such as NF-kB and cyclin D1 [ 6 , 12 ], which are key pathways, involved in breast cancer development [ 6 , 12 ]. Very recent studies conducted in Europe demonstrated that elevated serum RANKL levels are associated with increased breast cancer risk among women with high progesterone levels [ 24 ], while another study reported that elevated OPG levels are associated with increased breast cancer risk [ 25 ]. Our study adds to findings from these initial studies indicating that the RANK pathway plays an important role in breast cancer development.…”

Section: Discussionmentioning

confidence: 99%

Increased breast tissue receptor activator of nuclear factor-κB ligand (RANKL) gene expression is associated with higher mammographic density in premenopausal women

et al. 2017

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Increased mammographic breast density is associated with a 4–6-fold increased risk of breast cancer, yet lifestyle factors that can reduce dense breasts are yet to be identified, and viable prevention strategies to reduce breast density-associated breast cancer development are yet to be developed. We investigated the associations of breast tissue receptor activator of nuclear factor-κB (RANK) pathway gene expression with mammographic density in 48 premenopausal women, with no previous history of cancer. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast tissue samples, using the NanoString nCounter platform. Mammographic density was classified based on the American College of Radiology Breast Imaging Reporting and Data (BI-RADS). Linear regression was used to evaluate associations between gene expression and mammographic density. The mean age of participants was 44.4 years. Women with higher breast tissue RANKL (TNFSF11) (p-value = 0.0076), and TNF (p-value = 0.007) gene expression had higher mammographic density. Our finding provides mechanistic support for a breast cancer chemoprevention trial with a RANKL inhibitor among high-risk premenopausal women with dense breasts.

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“…There was a modest reduction in risk (0.84) of ER+ breast cancer with high OPG (T1-342, T2-297, T3-290 cases). When comparing these data with Vik et al it appears that the range of OPG values are much lower in the Fortner et al study (17,18). The Vik et al study.…”

Section: Opg Protein Serum Levels and Breast Cancer Riskmentioning

confidence: 61%

“…OPG expression vs. breast cancer risk has been analyzed in a more recent, similar type of study (18). The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was a study designed to identify risk factors for cancer.…”

Section: Opg Protein Serum Levels and Breast Cancer Riskmentioning

confidence: 99%

Osteoprotegerin: Relationship to Breast Cancer Risk and Prognosis

2020

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Osteoprotegerin (OPG) is a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily (TNFRSF11B), that was first characterized and named for its protective role in bone remodeling. In this context, OPG binds to another TNF superfamily member Receptor Activator of NF-kappaB Ligand (RANKL; TNFSF11) and blocks interaction with RANK (TNFRSF11A), preventing RANKL/RANK stimulation of osteoclast maturation, and bone breakdown. Further studies revealed that OPG protein is also expressed by tumor cells and led to investigation of the role of OPG in tumor biology. An increasing body of data has demonstrated that OPG modulates breast tumor behavior. Initially, research was focused on OPG in the bone microenvironment as a potential inhibitor of RANKL-driven osteolysis. More recently, attention has shifted to include OPG expression and interactions in the primary breast tumor independent of RANKL. In the primary tumor, OPG may interact with another TNF superfamily member, TNF-Related Apoptosis Inducing Ligand (TRAIL; TNFSF10) to prevent apoptosis induction. Additional interest in OPG in breast cancer has been stimulated by the tumor-promoting role of its binding partner RANKL in association with BRCA1 gene mutations. We and others have previously summarized the functional studies on OPG and breast cancer (1, 2). After basic research studies on the in vitro role for OPG (and RANKL) in breast cancer, the field now expands to assess the in vivo role for OPG by examining the correlation between OPG expression and breast cancer risk or patient prognosis. However, the data reported so far is conflicting, since OPG expression appears linked to both good and poor patient survival. In the current review we will summarize these studies. Our goal is to provide stimulus for further research to bridge the basic research findings and clinical data regarding OPG in breast cancer.

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Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

Cited by 23 publications

References 68 publications

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Increased breast tissue receptor activator of nuclear factor-κB ligand (RANKL) gene expression is associated with higher mammographic density in premenopausal women

Osteoprotegerin: Relationship to Breast Cancer Risk and Prognosis

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