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DOI: 10.1055/s-0031-1298276
RANK, RANKL and OPG Expression in Breast Cancer – Influence on Osseous Metastasis
RANK-, RANKL- und OPG-Expression beim Mammakarzinom – Einfluss auf ossäre MetastasierungPublication History
received 19 July 2011
revised 19 December 2011
accepted 21 December 2011
Publication Date:
30 May 2012 (online)
![](https://www.thieme-connect.de/media/gebfra/201205/lookinside/thumbnails/10.1055-s-0031-1298276-1.jpg)
Abstract
In women, malignant breast tumours are among the most common malignant diseases in Europe. In advanced breast cancer, the risk of bone metastasis increases to 65–75 %. The discovery of the physiological bone metabolism parameters RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) and OPG (osteoprotegerin) as well as their pathophysiological involvement in bone-related diseases is the subject of new therapeutic strategies. The formation of osteolytic bone metastasis requires increased osteoclast activity. Activation of osteoclasts by excessive direct RANKL or reduced OPG expression of osseous metastatic tumour cells remains to be elucidated. More than 50 % of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14–60 %. Increased OPG concentrations in the serum of patients with bone metastases have been shown in several studies, whereas the RANKL results are described in an opposite manner. The use of OPG as a biomarker for the detection of osteolytic bone metastases is not consistent and needs to be proved in further studies. Increased RANKL activity was found in diseases characterised by excessive bone loss and formed the basis of new therapeutic options. In several studies, a human monoclonal antibody to RANKL (denosumab) was investigated for the treatment of bone diseases. Denosumab is a promising therapeutic option due to its bone-protective effects.
Zusammenfassung
Maligne Erkrankungen der Brust zählen in Europa zu den häufigsten bösartigen Tumoren bei Frauen. Bei fortgeschrittenem Brustkrebs erhöht sich das Risiko einer Knochenmetastase auf 65–75 %. Die Entdeckung der physiologischen Knochenstoffwechselparameter RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) und OPG (osteoprotegerin) sowie deren pathophysiologische Beteiligung bei ossär bedingten Erkrankungen ist Gegenstand neuer Therapiestrategien. Gerade die Entstehung von osteolytischen Knochenmetastasen setzt eine gesteigerte Osteoklastenaktivität voraus. Eine Aktivierung der Osteoklasten durch übermäßige direkte RANKL- oder reduzierte OPG-Expression ossär metastasierter Tumorzellen ist bis heute nicht eindeutig geklärt. In über 50 % der Fälle exprimierten primäre Mammakarzinomzellen OPG und RANK, während RANKL in nur 14–60 % nachgewiesen werden konnte. Erhöhte OPG-Konzentrationen im Serum von Patientinnen mit Knochenmetastasen konnten in mehreren Studien gezeigt werden, während die RANKL-Resultate gegensätzlich beschrieben sind. Eine Verwendung von OPG als Biomarker zur Detektion von osteolytischen Knochenmetastasen ist nicht einheitlich und muss durch weitere Studien belegt werden. Eine erhöhte RANKL-Aktivität konnte bei Krankheiten mit ausgedehntem Knochenverlust gefunden werden und bildete die Grundlage neuer Therapieoptionen. In mehreren Studien wurde ein humaner monoklonaler Antikörper gegen RANKL (Denosumab) zur Behandlung ossär bedingter Erkrankungen untersucht. Denosumab stellt wegen seiner knochenprotektiven Wirkung eine vielversprechende Therapieoption dar.
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References
- 1 Keck AV, Pecherstorfer M. Knochenstoffwechsel bei malignen Erkrankungen. J Miner Stoffwechs 2003; 10: 6-11
- 2 Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010; 285: 25103-25108
- 3 Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4: 638-649
- 4 Kong YY, Feige U, Sarosi I et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402: 304-309
- 5 Lacey DL, Timms E, Tan HL et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-176
- 6 Lum L, Wong BR, Josien R et al. Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 1999; 274: 13613-13618
- 7 Fuller K, Wong B, Fox S et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998; 188: 997-1001
- 8 OʼBrien EA, Williams JH, Marshall MJ. Osteoprotegerin ligand regulates osteoclast adherence to the bone surface in mouse calvaria. Biochem Biophys Res Commun 2000; 274: 281-290
- 9 Anderson DM, Maraskovsky E, Billingsley WL et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997; 390: 175-179
- 10 Hsu H, Lacey DL, Dunstan CR et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96: 3540-3545
- 11 Dougall WC, Glaccum M, Charrier K et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13: 2412-2424
- 12 Kong YY, Yoshida H, Sarosi I et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315-323
- 13 Stolina M, Dwyer D, Ominsky MS et al. Continuous RANKL inhibition in osteoprotegerin transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses. J Immunol 2007; 179: 7497-7505
- 14 Mizuno A, Kanno T, Hoshi M et al. Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis. J Bone Miner Metab 2002; 20: 337-344
- 15 Lloyd SA, Yuan YY, Kostenuik PJ et al. Soluble RANKL induces high bone turnover and decreases bone volume, density, and strength in mice. Calcif Tissue Int 2008; 82: 361-372
- 16 Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
- 17 Tsuda E, Goto M, Mochizuki S et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997; 234: 137-142
- 18 Yamaguchi K, Kinosaki M, Goto M et al. Characterization of structural domains of human osteoclastogenesis inhibitory factor. J Biol Chem 1998; 273: 5117-5123
- 19 Gori F, Hofbauer LC, Dunstan CR et al. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology 2000; 141: 4768-4776
- 20 Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand. J Biol Chem 2005; 280: 41155-41164
- 21 Shalhoub V, Faust J, Boyle WJ et al. Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors. J Cell Biochem 1999; 72: 251-261
- 22 Bucay N, Sarosi I, Dunstan CR et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-1268
- 23 Quattrocchi CC, Piciucchi S, Sammarra M et al. Bone metastases in breast cancer: higher prevalence of osteosclerotic lesions. Radiol Med 2007; 112: 1049-1059
- 24 Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483-2494
- 25 Charhon SA, Chapuy MC, Delvin EE et al. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer 1983; 51: 918-924
- 26 Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005; 12: 549-583
- 27 Goltzman D. Osteolysis and cancer. J Clin Invest 2001; 107: 1219-1220
- 28 Bendre MS, Margulies AG, Walser B et al. Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 2005; 65: 11001-11009
- 29 Perez M, Migliaccio S, Taranta A et al. Melanoma cells stimulate osteoclastogenesis, c-Src expression and osteoblast cytokines. Eur J Cancer 2001; 37: 629-640
- 30 Thomas RJ, Guise TA, Yin JJ et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 1999; 140: 4451-4458
- 31 Blum B, Moseley J, Miller L et al. Measurement of bone morphogenetic proteins and other growth factors in demineralized bone matrix. Orthopedics 2004; 27: s161-s165
- 32 Guise TA, Chirgwin JM. Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res 2003; S32-S38
- 33 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002; 2: 584-593
- 34 Park HR, Min SK, Cho HD et al. Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis. J Korean Med Sci 2003; 18: 541-546
- 35 Schubert A, Schulz H, Emons G et al. Expression of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in HCC70 breast cancer cells and effects of treatment with gonadotropin-releasing hormone on RANKL expression. Gynecol Endocrinol 2008; 24: 331-338
- 36 Reinholz MM, Iturria SJ, Ingle JN et al. Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 2002; 74: 255-269
- 37 Nicolin V, Bortul R, Bareggi R et al. Breast adenocarcinoma MCF-7 cell line induces spontaneous osteoclastogenesis via a RANK-ligand-dependent pathway. Acta Histochem 2008; 110: 388-396
- 38 Nicolin V, Narducci P. Soluble TRAIL could enhance bone destruction acting on Rank-ligand in estrogen-independent human breast cancer cell line MDA-MB-231. Acta Histochem 2010; 112: 189-192
- 39 Bhatia P, Sanders MM, Hansen MF. Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res 2005; 11: 162-165
- 40 Santini D, Perrone G, Roato I et al. Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol 2011; 226: 780-784
- 41 Trinkaus M, Ooi WS, Amir E et al. Examination of the mechanisms of osteolysis in patients with metastatic breast cancer. Oncol Rep 2009; 21: 1153-1159
- 42 Santini D, Schiavon G, Vincenzi B et al. Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One 2011; 6: e19234
- 43 Van Poznak C, Cross SS, Saggese M et al. Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. J Clin Pathol 2006; 59: 56-63
- 44 Cross SS, Harrison RF, Balasubramanian SP et al. Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. J Clin Pathol 2006; 59: 716-720
- 45 Huang L, Cheng YY, Chow LT et al. Tumour cells produce receptor activator of NF-kappaB ligand (RANKL) in skeletal metastases. J Clin Pathol 2002; 55: 877-878
- 46 Holen I, Cross SS, Neville-Webbe HL et al. Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo – a role in tumour cell survival?. Breast Cancer Res Treat 2005; 92: 207-215
- 47 Jones DH, Nakashima T, Sanchez OH et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006; 440: 692-696
- 48 Emery JG, McDonnell P, Burke MB et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14363-14367
- 49 Vitovski S, Phillips JS, Sayers J et al. Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways. J Biol Chem 2007; 282: 31601-31609
- 50 Lipton A, Ali SM, Leitzel K et al. Serum osteoprotegerin levels in healthy controls and cancer patients. Clin Cancer Res 2002; 8: 2306-2310
- 51 Mountzios G, Dimopoulos MA, Bamias A et al. Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. Acta Oncol 2007; 46: 221-229
- 52 Mercatali L, Ibrahim T, Sacanna E et al. Bone metastases detection by circulating biomarkers: OPG and RANK-L. Int J Oncol 2011; 39: 255-261
- 53 Leeming DJ, Koizumi M, Byrjalsen I et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomarkers Prev 2006; 15: 32-38
- 54 Martinetti A, Bajetta E, Ferrari L et al. Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrozole. Endocr Relat Cancer 2004; 11: 771-779
- 55 Yano K, Tsuda E, Washida N et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 1999; 14: 518-527
- 56 Mountzios G, Terpos E, Syrigos K et al. Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. Transl Res 2010; 155: 247-255
- 57 Bekker PJ, Holloway D, Nakanishi A et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001; 16: 348-360
- 58 Body JJ, Greipp P, Coleman RE et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97: 887-892
- 59 Bekker PJ, Holloway DL, Rasmussen AS et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. 2004. J Bone Miner Res 2005; 20: 2275-2282
- 60 Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005; 5: 618-625
- 61 Eastell R, Christiansen C, Grauer A et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 2011; 26: 530-537
- 62 McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821-831
- 63 Deodhar A, Dore RK, Mandel D et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2010; 62: 569-574
- 64 Dore RK, Cohen SB, Lane NE et al. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69: 872-875
- 65 Body JJ, Facon T, Coleman RE et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006; 12: 1221-1228
- 66 Lipton A, Steger GG, Figueroa J et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007; 25: 4431-4437
- 67 Lipton A, Steger GG, Figueroa J et al. Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 2008; 14: 6690-6696
- 68 Fizazi K, Lipton A, Mariette X et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009; 27: 1564-1571
- 69 Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28: 5132-5139
- 70 Ellis GK, Bone HG, Chlebowski R et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 2009; 118: 81-87
- 71 Sterling JA, Edwards JR, Martin TJ et al. Advances in the biology of bone metastasis: how the skeleton affects tumor behavior. Bone 2010; 48: 6-15