Metformin inhibits RANKL and sensitizes cancer stem cells to denosumab

References

• Kobayashi Y, Udagawa N, Takahashi N. Action of RANKL and OPG for osteoclastogenesis. Crit Rev Eukaryot Gene Expr 2009; 19:61-72; PMID:19191757; https://doi.org/10.1615/CritRevEukarGeneExpr.v19.i1.30
   PubMed Web of Science ®Google Scholar
• Martin TJ, Sims NA. RANKL/OPG; Critical role in bone physiology. Rev Endocr Metab Disord 2015; 16:131-9; PMID:25557611; https://doi.org/10.1007/s11154-014-9308-6
   PubMed Web of Science ®Google Scholar
• Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 2012; 11:401-19; PMID:22543469; https://doi.org/10.1038/nrd3705
   PubMed Web of Science ®Google Scholar
• Brown-Glaberman U, Stopeck AT. Impact of denosumab on bone mass in cancer patients. Clin Pharmacol 2013; 5:117-29; PMID:23861604.
   PubMedGoogle Scholar
• Gül G, Sendur MA, Aksoy S, Sever AR, Altundag K. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr Med Res Opin 2016; 32:133-45; PMID:26451465; https://doi.org/10.1185/03007995.2015.1105795
   PubMed Web of Science ®Google Scholar
• Dougall WC, Holen I, González Suárez E. Targeting RANKL in metastasis. Bonekey Rep 2014; 3:519; PMID:24795813; https://doi.org/10.1038/bonekey.2014.14
   PubMedGoogle Scholar
• Widschwendter M, Burnell M, Fraser L, Rosenthal AN, Philpott S, Reisel D, Dubeau L, Cline M, Pan Y, Yi PC, Gareth Evans D, Jacobs IJ, Menon U, Wood CE, Dougall WC. Osteoprotegerin (OPG), The endogenous inhibitor of receptor activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA mutation carriers. EBioMedicine 2015; 2:1331-9; PMID:26629528; https://doi.org/10.1016/j.ebiom.2015.08.037
   PubMed Web of Science ®Google Scholar
• Odén L, Akbari M, Zaman T, Singer CF, Sun P, Narod SA, Salmena L, Kotsopoulos J. Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Oncotarget 2016; 7:86687-86694; PMID:27893411.
   PubMed Web of Science ®Google Scholar
• Kiechl S, Schramek D, Widschwendter M, Fourkala EO, Zaikin A, Jones A, Jaeger B, Rack B, Janni W, Scholz C, Willeit J, Weger S, Mayr A, Teschendorff A, Rosenthal A, Fraser L, Philpott S, Dubeau L, Keshtgar M, Roylance R, Jacobs IJ, Menon U, Schett G, Penninger JM. Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. Oncotarget 2017; 8:3811-3825; PMID:28002811.
   PubMed Web of Science ®Google Scholar
• Kotsopoulos J, Singer C, Narod SA. Can we prevent BRCA1-associated breast cancer by RANKL inhibition?. Breast Cancer Res Treat 2017; 161:11-16; PMID:27783278; https://doi.org/10.1007/s10549-016-4029-z
   PubMed Web of Science ®Google Scholar
• Sigl V, Owusu-Boaitey K, Joshi PA, Kavirayani A, Wirnsberger G, Novatchkova M, Kozieradzki I, Schramek D, Edokobi N, Hersl J, Sampson A, Odai-Afotey A, Lazaro C, Gonzalez-Suarez E, Pujana MA, Cimba F, Heyn H, Vidal E, Cruickshank J, Berman H, Sarao R, Ticevic M, Uribesalgo I, Tortola L, Rao S, Tan Y, Pfeiler G, Lee EY, Bago-Horvath Z, Kenner L, Popper H, Singer C, Khokha R, Jones LP, Penninger JM. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 2016; 26:761-74; PMID:27241552; https://doi.org/10.1038/cr.2016.69
   PubMed Web of Science ®Google Scholar
• Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 2016; 22:933-9; PMID:27322743; https://doi.org/10.1038/nm.4118
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Corominas-Faja B, Muñoz-San Martín M, Martin-Castillo B, Lupu R, Brunet J, Bosch-Barrera J, Menendez JA. BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells. Oncotarget 2017; [epub ahead of print]; PMID:28388533; https://doi.org/10.18632/oncotarget.16558
   PubMed Web of Science ®Google Scholar
• Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget 2011; 2:896-917; PMID:22203527; https://doi.org/10.18632/oncotarget.387
   PubMed Web of Science ®Google Scholar
• Chae YK, Arya A, Malecek MK, Shin DS, Carneiro B, Chandra S, Kaplan J, Kalyan A, Altman JK, Platanias L, Giles F. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 2016; 7:40767-40780; PMID:27004404.
   PubMed Web of Science ®Google Scholar
• Menendez JA, Martin-Castillo B, Joven J. Metformin and cancer: Quo vadis et cui bono?. Oncotarget 2016; 7:54096-54101.
   PubMed Web of Science ®Google Scholar
• Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L. Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 2006; 536:38-46; PMID:16564524; https://doi.org/10.1016/j.ejphar.2006.02.030
   PubMed Web of Science ®Google Scholar
• Lee YS, Kim YS, Lee SY, Kim GH, Kim BJ, Lee SH, Lee KU, Kim GS, Kim SW, Koh JM. AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts. Bone 2010; 47:926-37; PMID:20696287; https://doi.org/10.1016/j.bone.2010.08.001
   PubMed Web of Science ®Google Scholar
• Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011; 112:2902-9; PMID:21618594; https://doi.org/10.1002/jcb.23206
   PubMed Web of Science ®Google Scholar
• Liu L, Zhang C, Hu Y, Peng B. Protective effect of metformin on periapical lesions in rats by decreasing the ratio of receptor activator of nuclear factor kappa B ligand/osteoprotegerin. J Endod 2012; 38:943-7; PMID:22703658; https://doi.org/10.1016/j.joen.2012.03.010
   PubMed Web of Science ®Google Scholar
• Wang J, Chen TY, Qin S, Duan Y, Wang G. Inhibitory effect of metformin on bone metastasis of cancer via OPG/RANKL/RANK system. Med Hypotheses 2013; 81:805-6; PMID:24074896; https://doi.org/10.1016/j.mehy.2013.08.032
   PubMed Web of Science ®Google Scholar
• Konishi H, Mohseni M, Tamaki A, Garay JP, Croessmann S, Karnan S, Ota A, Wong HY, Konishi Y, Karakas B, Tahir K, Abukhdeir AM, Gustin JP, Cidado J, Wang GM, Cosgrove D, Cochran R, Jelovac D, Higgins MJ, Arena S, Hawkins L, Lauring J, Gross AL, Heaphy CM, Hosokawa Y, Gabrielson E, Meeker AK, Visvanathan K, Argani P, Bachman KE, Park BH. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci U S A 2011; 108:17773-8; PMID:21987798; https://doi.org/10.1073/pnas.1110969108
   PubMed Web of Science ®Google Scholar
• Menendez JA, Folguera-Blasco N, Cuyàs E, Fernández-Arroyo S, Joven J, Alarcón T. Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome. Oncotarget 2016; 7:11959-71; PMID:26943589.
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Fernández-Arroyo S, Alarcón T, Lupu R, Joven J, Menendez JA. Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: evidence for metformin-based “starvation” strategies in BRCA1 carriers. Oncotarget 2016; 7:52974-52992; PMID:27259235.
   PubMed Web of Science ®Google Scholar
• Elstrodt F, Hollestelle A, Nagel JH, Gorin M, Wasielewski M, van den Ouweland A, Merajver SD, Ethier SP, Schutte M. BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res 2006; 66:41-5; PMID:16397213; https://doi.org/10.1158/0008-5472.CAN-05-2853
   PubMed Web of Science ®Google Scholar
• Ottewell PD, Woodward JK, Lefley DV, Evans CA, Coleman RE, Holen I. Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. Mol Cancer Ther 2009; 8:2821-32; PMID:19789217; https://doi.org/10.1158/1535-7163.MCT-09-0462
   PubMed Web of Science ®Google Scholar
• Wright LE, Ottewell PD, Rucci N, Peyruchaud O, Pagnotti GM, Chiechi A, Buijs JT, Sterling JA. Murine models of breast cancer bone metastasis. Bonekey Rep 2016; 5:804; PMID:27867497; https://doi.org/10.1038/bonekey.2016.31
   PubMed Web of Science ®Google Scholar
• Sohn W, Simiens MA, Jaeger K, Hutton S, Jang G. The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: A systematic review. Br J Clin Pharmacol 2014; 78:477-87; PMID:24548274; https://doi.org/10.1111/bcp.12355
   PubMed Web of Science ®Google Scholar
• Nolan E, Lindeman GJ, Visvader JE. Out-RANKing BRCA1 in mutation carriers. Cancer Res 2017; 77:595-600; PMID:28104682; https://doi.org/10.1158/0008-5472.CAN-16-2025
   PubMed Web of Science ®Google Scholar
• Walcott FL, Patel J, Lubet R, Rodriguez L, Calzone KA. Hereditary cancer syndromes as model systems for chemopreventive agent development. Semin Oncol 2016; 43:134-45; PMID:26970132; https://doi.org/10.1053/j.seminoncol.2015.09.015
   PubMed Web of Science ®Google Scholar
• McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes 2016; 7:122-33; PMID:27022443; https://doi.org/10.4239/wjd.v7.i6.122
   PubMed Web of Science ®Google Scholar
• Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer CG, Thomas DG, Hayes DF, Korkaya H, Wicha MS. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: Implications for efficacy of adjuvant trastuzumab. Cancer Res 2013; 73:1635-46; PMID:23442322; https://doi.org/10.1158/0008-5472.CAN-12-3349
   PubMed Web of Science ®Google Scholar
• Coleman RE. Bone cancer in 2011: Prevention and treatment of bone metastases. Nat Rev Clin Oncol 2011; 9:76-8; PMID:22182971; https://doi.org/10.1038/nrclinonc.2011.198
   PubMed Web of Science ®Google Scholar
• Klijn C, Durinck S, Stawiski EW, Haverty PM, Jiang Z, Liu H, Degenhardt J, Mayba O, Gnad F, Liu J, Pau G, Reeder J, Cao Y, Mukhyala K, Selvaraj SK, Yu M, Zynda GJ, Brauer MJ, Wu TD, Gentleman RC, Manning G, Yauch RL, Bourgon R, Stokoe D, Modrusan Z, Neve RM, de Sauvage FJ, Settleman J, Seshagiri S, Zhang Z. A comprehensive transcriptional portrait of human cancer cell lines. Nat Biotechnol 2015; 33:306-12; PMID:25485619; https://doi.org/10.1038/nbt.3080
   PubMed Web of Science ®Google Scholar
• Pavlovic M, Arnal-Estapé A, Rojo F, Bellmunt A, Tarragona M, Guiu M, Planet E, Garcia-Albéniz X, Morales M, Urosevic J, Gawrzak S, Rovira A, Prat A, Nonell L, Lluch A, Jean-Mairet J, Coleman R, Albanell J, Gomis RR. Enhanced MAF oncogene expression and breast cancer bone metastasis. J Natl Cancer Inst 2015; 107(12):djv256; PMID:26376684; https://doi.org/10.1093/jnci/djv256
   PubMedGoogle Scholar
• Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126:355-64; PMID:20458531; https://doi.org/10.1007/s10549-010-0924-x
   PubMed Web of Science ®Google Scholar
• Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 2010; 9:3807-14; PMID:20890129; https://doi.org/10.4161/cc.9.18.13131
   PubMed Web of Science ®Google Scholar
• Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, Martin-Castillo B, Menendez JA. Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget 2012; 3:395-8; PMID:22565037; https://doi.org/10.18632/oncotarget.488
   PubMed Web of Science ®Google Scholar