• RANK/RANKL/OPG pathway
• breast cancer
• breast cancer cell lines
• breast cancer stem cells
• mammospheres

• Humans
• RANK Ligand/metabolism
• RANK Ligand/genetics
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Receptor Activator of Nuclear Factor-kappa B/genetics
• Osteoprotegerin/metabolism
• Osteoprotegerin/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/genetics
• Female
• Signal Transduction
• Gene Expression Regulation, Neoplastic
• MCF-7 Cells
• Cell Line, Tumor

• The authors received no specific funding for this work.

• Breast cancer
• Denosumab
• Immunotherapy
• Mammary gland
• RANK
• RANKL

• Humans
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• RANK Ligand/metabolism
• RANK Ligand/genetics
• RANK Ligand/antagonists & inhibitors
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Receptor Activator of Nuclear Factor-kappa B/genetics
• Signal Transduction/drug effects
• Female
• Animals
• Tumor Microenvironment
• Denosumab/therapeutic use

• Breast cancer
• Immunohistochemistry
• Mammographic density
• RANK expression
• RANKL expression

• Humans
• RANK Ligand/metabolism
• RANK Ligand/analysis
• Female
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/diagnostic imaging
• Middle Aged
• Breast Density
• Aged
• Adult
• Case-Control Studies
• Immunohistochemistry
• Tissue Array Analysis
• Breast/diagnostic imaging
• Breast/pathology
• Breast/metabolism

• BCRF-22-132 Breast Cancer Research Foundation
• BCRP 12IB-0155 California Breast Cancer Research Program
• Bayerisch-Kalifornisches Hochschulzentrum
• Deutsche Krebshilfe
• Universitätsklinikum Erlangen (8546)

• Bone cancer
• Bone metastasis
• Cancer-induced bone pain
• Lysophosphatidic acid

• Humans
• Lysophospholipids/metabolism
• Bone Neoplasms/secondary
• Bone Neoplasms/metabolism
• Bone Neoplasms/drug therapy
• Bone Neoplasms/pathology
• Signal Transduction/drug effects
• Receptors, Lysophosphatidic Acid/metabolism
• Receptors, Lysophosphatidic Acid/genetics
• Animals

• Cancer-associated fibroblasts
• RANK/RANKL
• breast cancer
• metastatic occurrence
• prognostic factor

• Humans
• Female
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Breast Neoplasms/mortality
• Breast Neoplasms/genetics
• Cancer-Associated Fibroblasts/metabolism
• Cancer-Associated Fibroblasts/pathology
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Prognosis
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Neoplasm Staging
• Neoplasm Metastasis
• Middle Aged
• Tumor Microenvironment
• RANK Ligand/metabolism
• RANK Ligand/genetics
• Adult
• Aged
• Cell Line, Tumor

• RANK
• RANKL
• breast cancer
• immunohistochemistry
• prognosis

• OPG
• RANKL
• bone invasion
• head and neck squamous cell carcinoma
• mandibular invasion
• osteoclasts

• Cancer treatment
• FOXP3
• Immune checkpoint
• Immune system
• RANKL

• Female
• Animals
• Mice
• Programmed Cell Death 1 Receptor
• B7-H1 Antigen
• BCG Vaccine/therapeutic use
• Non-Muscle Invasive Bladder Neoplasms
• Administration, Intravesical
• Urinary Bladder Neoplasms/pathology
• Adjuvants, Immunologic/therapeutic use
• Signal Transduction
• Neoplasm Recurrence, Local/pathology
• Neoplasm Invasiveness

• 001 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• 2018/10052-1 Fundação de Amparo à Pesquisa do Estado de São Paulo
• 552120/2011-1 Conselho Nacional de Desenvolvimento Científico e Tecnológico

• A. capillus-veneris L.
• GC-MS
• carbendazim
• hepatotoxicity
• protection
• rats

• Rats
• Humans
• Animals
• Antioxidants/pharmacology
• Antioxidants/metabolism
• Adiantum/chemistry
• Adiantum/metabolism
• Plant Extracts/pharmacology
• Plant Extracts/metabolism
• Inflammation/metabolism
• Oxidative Stress
• Liver
• Chemical and Drug Induced Liver Injury/metabolism

• RSP2023R504 King Saud University

Most of breast cancer cases are sporadic; however, 15–20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care – from cancer prevention and early detection, through active treatment and up to survivorship issues.

The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER⁺), progesterone receptor-positive (PR⁺), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

• Biology
• Bone Resorption/pathology
• Bone and Bones/pathology
• Humans
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Receptor Activator of Nuclear Factor-kappa B/metabolism

• R01 AI125284 NIAID NIH HHS
• R01 AR069546 NIAMS NIH HHS
• R01 AR077526 NIAMS NIH HHS
• R01 AR080021 NIAMS NIH HHS

The endocannabinoid system has been postulated to help restrict cancer progression and maintain osteoblastic function during bone metastasis. Herein, the effects of cannabinoid receptor (CB) type 1 and 2 activation on breast cancer cell and osteoblast interaction were investigated by using ACEA and GW405833 as CB1 and CB2 agonists, respectively. Our results showed that breast cancer cell (MDA-MB-231)-derived conditioned media markedly decreased osteoblast-like UMR-106 cell viability. In contrast, media from MDA-MB-231 cells pre-treated with GW405833 improved UMR-106 cell viability. MDA-MB-231 cells were apparently more susceptible to both CB agonists than UMR-106 cells. Thereafter, we sought to answer the question as to how CB agonists reduced MDA-MB-231 cell virulence. Present data showed that co-activation of CB1 and CB2 exerted cytotoxic effects on MDA-MB-231 cells by increasing apoptotic cell death through suppression of the NF-κB signaling pathway in an ROS-independent mechanism. ACEA or GW405833 alone or in combination also inhibited MDA-MB-231 cell migration. Thus, it can be concluded that the endocannabinoid system is able to provide protection during breast cancer bone metastasis by interfering cancer and bone cell interaction as well as by the direct suppression of cancer cell growth and migration.

The receptor activator of nuclear factor kappa B (RANK) is becoming recognized as a master regulator of tumorigenesis, yet its role in gynecological cancers remains mostly unexplored. We investigated whether there is a gradation of RANK protein and mRNA expression in epithelial ovarian cancer (EOC) according to malignancy and tumor staging. Immunohistochemical expression of RANK was examined in a cohort of 135 (benign n = 29, borderline n= 23 and malignant n = 83) EOCs. Wild type and truncated RANK mRNA isoform quantification was performed in a cohort of 168 (benign n = 26, borderline n = 13 and malignant n = 129) EOCs. RANK protein and mRNA values were increased in malignant vs. benign or borderline conditions across serous, mucinous and endometrioid cancer subtypes. Additionally, a trend of increased RANK values with staging was observed for the mucinous and serous histotype. Thus, increased expression of RANK appears associated with the evolution of disease to the onset of malignancy in EOC. Moreover, in some EOC histotypes, RANK expression is additionally associated with clinicopathological markers of tumor aggressiveness, suggesting a role in further progression of tumor activity.

• RANK
• epithelial ovarian cancers
• immunohistochemistry
• tumor stage, tumor grade

• Carcinoma, Ovarian Epithelial/pathology
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Grading
• Neoplasm Staging
• Ovarian Neoplasms/pathology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptor Activator of Nuclear Factor-kappa B/genetics
• Receptor Activator of Nuclear Factor-kappa B/metabolism

• Bone
• McCune albright
• RANK/RANKL
• craniofacial
• denosumab
• fibrous dysplasia
• oxidative stress

• ageing
• bone
• endothelial cell
• joint
• vascular niche

• Aging/immunology
• Aging/metabolism
• Aging/pathology
• Animals
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/metabolism
• Arthritis, Rheumatoid/pathology
• Blood Vessels/immunology
• Blood Vessels/metabolism
• Blood Vessels/pathology
• Bone Diseases/immunology
• Bone Diseases/metabolism
• Bone Diseases/pathology
• Bone Neoplasms/immunology
• Bone Neoplasms/metabolism
• Bone Neoplasms/pathology
• Bone and Bones/blood supply
• Cell Differentiation
• Cell Proliferation
• Endothelial Progenitor Cells/immunology
• Endothelial Progenitor Cells/metabolism
• Endothelial Progenitor Cells/pathology
• Hematopoietic Stem Cells/immunology
• Hematopoietic Stem Cells/metabolism
• Hematopoietic Stem Cells/pathology
• Homeostasis
• Humans
• Joints/blood supply
• Osteoarthritis/immunology
• Osteoarthritis/metabolism
• Osteoarthritis/pathology
• Phenotype
• Stem Cell Niche

• MR/P02209X/1 Medical Research Council
• European Research Council
• Medical Research Council

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Despite the emergence of new therapeutic agents in recent years, curation remains challenging, and new and better treatment options are needed. In the present study, we investigated the expression, prognostic significance, and functional role of the Receptor Activator of Nuclear Factor-κB (RANK) in AML. We found that RANK is expressed on leukemic cells in a substantial proportion of AML patients and is associated with a dismal disease course. We further demonstrated that signaling via RANK induces release of factors that favor AML cell survival and confers resistance to chemotherapeutics in AML treatment. Together, our findings identify RANK as novel prognostic marker and putative candidate for therapeutic intervention in AML to enhance response to treatment.

Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as “functional” prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.

• AML
• RANK
• chemotherapy resistance
• cytarabine
• doxorubicin
• prognosis

• 310030A 176256 Swiss National Science Foundation

The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

• RANK ligand (RANKL)
• bone metastasis
• bone-targeted agent
• breast cancer
• drug repurposing
• receptor activator of nuclear factor-κB (RANK)
• targeted therapy

• Bone metastases
• Immune response
• Molecular subtypes
• Muscle-invasive bladder cancer
• RANK

• Breast cancer
• HER2
• Lapatinib
• NF-κB
• RANK
• RANKL
• Resistance
• Trastuzumab

• Bone metastasis
• Osteoblast
• Osteoclast
• RANKL
• Tumor

• Animals
• Bone Neoplasms/metabolism
• Bone Neoplasms/pathology
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Clinical Trials as Topic
• Humans
• Neoplasm Metastasis
• Osteoblasts/metabolism
• Osteoblasts/pathology
• RANK Ligand/metabolism

• bisphosphonate
• denosumab
• dormancy
• immunosurveillance
• metastatic niche

In the present study, we investigated various biochemical, clinical, and histological factors associated with bone metastases in a large cohort of pre- and postmenopausal women with breast cancer. Two hundred and sixty-one consecutive women with breast cancer were included in this study. Breast adipose tissue specimens were collected during surgery. After having established the fatty acid profile of breast adipose tissue by gas chromatography, we determined whether there were differences associated with the occurrence of bone metastases in these patients. Regarding the clinical and histological criteria, a majority of the patients with bone metastases (around 70%) had tumors with a luminal phenotype and 59% of them showed axillary lymph node involvement. Moreover, we found a negative association between the levels of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in breast adipose tissue and the development of bone metastases in premenopausal women. No significant association was observed in postmenopausal women. In addition to a luminal phenotype and axillary lymph node involvement, low levels of n-3 LC-PUFA in breast adipose tissue may constitute a risk factor that contributes to breast cancer bone metastases formation in premenopausal women.

• adipose tissue
• bone metastases
• breast cancer
• n-3 long-chain polyunsaturated fatty acids

• Gastric cancer
• NF-κB
• Transcribed ultraconserved region
• Uc.63+

• Bone cancer
• Pathogenesis

• This work is supported by the National Natural Science Foundation of China (No. 81602492), National Key Research and Development Program of China (No. 2016YFA0201402), and National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2018ZX09733001).

• CTCs
• DTCs
• bone metastases
• bone turnover markers
• ctDNA
• miRNAs

• 6877002
• CD40L
• Combination therapy
• NFκB
• RANKL

Receptor activator of nuclear factor-κB ligand (RANKL) is a key molecule that is expressed in bone stromal cells and is associated with metastasis and poor prognosis in many cancers. However, cancer cells that directly express RANKL have yet to be unveiled. The current study sought to evaluate how a single subunit of G protein, guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), transforms cancer cells into RANKL-expressing cancer cells.

We investigated the specific role of GNAQ using GNAQ wild-type cell lines (non-small-cell lung cancer cell lines; A549 cell lines), GNAQ knockdown cell lines, and patient-derived cancer cells. We evaluated GNAQ, RANKL, macrophage colony-stimulating factor (M-CSF), nuclear transcription factor-κB (NF-κB), inhibitor of NF-κB (IκB), and protein kinase B (Akt) signalling in the GNAQ wild-type and the GNAQ-knockdown cells. Osteoclastogenesis was also evaluated in both cell lines.

In the GNAQ-knockdown cells, RANKL expression was significantly upregulated (p < 0.001). The expression levels of M-CSF were also significantly increased in the GNAQ-knockdown cells compared with control cells (p < 0.001). GNAQ knockdown cells were highly sensitive to tumour necrosis factor alpha (TNF-α) and showed significant activation of the NF-κB pathway. The expression levels of RANKL were markedly increased in GNAQ mutant compared with GNAQ wild-type in patient-derived tumour tissues.

The present study reveals that the alterations of GNAQ activate NF-κB pathway in cancers, which increase RANKL and M-CSF expression and induce osteoclastogenesis in cancers.

Cite this article:Bone Joint Res. 2020;9(1):29–35.

• Bone
• GNAQ
• Lung cancer
• Osteoclastogenesis
• RANKL

• ER+ breast cancer
• RANKL-RANK pathway
• metastization
• resistance to chemo and hormone therapy
• stemness

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.

• TNF superfamily
• TNFRSF11B
• breast cancer
• osteoprotegerin (OPG)
• prognosis
• risk

• RANK
• RANKL
• bone metastasis
• breast cancer
• denosumab
• vicious cycle

• Bone health
• Bone remodeling
• RANKL/RANK/OPG system
• Zinc supplement

• Animals
• Bone Density/drug effects
• Bone and Bones/drug effects
• Bone and Bones/metabolism
• Humans
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Zinc/therapeutic use

• microrna-16 mimics
• microrna-16 inhibitor
• hypoxia/reoxygenation
• cytokine induced apoptosis inhibitor 1
• nuclear factor-κb pathway

• Animals
• Apoptosis Regulatory Proteins/biosynthesis
• Cell Line
• Down-Regulation
• Humans
• MicroRNAs
• Myocardial Reperfusion Injury/metabolism
• Myocardial Reperfusion Injury/pathology
• Myocardial Reperfusion Injury/prevention & control
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• NF-kappa B/metabolism
• Rats
• Signal Transduction

• Dietary polyphenols
• cancer
• nuclear factor-κB
• phosphorylation
• signaling pathway

• Apoptosis/drug effects
• Humans
• NF-kappa B/antagonists & inhibitors
• NF-kappa B/metabolism
• Neoplasms/diet therapy
• Neoplasms/metabolism
• Polyphenols/pharmacology
• Polyphenols/therapeutic use
• Signal Transduction/drug effects

• Cell growth
• Cell proliferation
• Organogenesis

• Adipose Tissue/metabolism
• Adipose Tissue/transplantation
• Animals
• Apoptosis
• Cell Line
• Cell Proliferation
• Cyclin D1/metabolism
• Epithelial Cells/metabolism
• Female
• Mammary Glands, Animal/growth & development
• Mammary Glands, Animal/metabolism
• Mice, Inbred BALB C
• Mice, Knockout
• NF-kappa B/metabolism
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphorylation
• Pregnancy
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Retinoblastoma Protein/metabolism
• Signal Transduction
• Stem Cells/metabolism
• TNF Receptor-Associated Factor 6/deficiency
• TNF Receptor-Associated Factor 6/genetics
• TNF Receptor-Associated Factor 6/metabolism

• MEXT | Japan Society for the Promotion of Science (JSPS)
• MEXT | JST | Adaptable and Seamless Technology Transfer Program through Target-Driven R and D (Adaptable and Seamless Technology Transfer Program through Target-Driven R&D)

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

• OPG
• RANK
• RANKL
• denosumab
• inflammation
• ovarian cancer