{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:24:38Z","timestamp":1777386278521,"version":"3.51.4"},"reference-count":80,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"Fundo Europeu de Desenvolvimento Regional funds","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-030158"],"award-info":[{"award-number":["POCI-01-0145-FEDER-030158"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"Fundo Europeu de Desenvolvimento Regional funds","doi-asserted-by":"publisher","award":["PTDC\/MED-PAT\/30158\/2017"],"award-info":[{"award-number":["PTDC\/MED-PAT\/30158\/2017"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Portuguese funds","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-030158"],"award-info":[{"award-number":["POCI-01-0145-FEDER-030158"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Portuguese funds","doi-asserted-by":"publisher","award":["PTDC\/MED-PAT\/30158\/2017"],"award-info":[{"award-number":["PTDC\/MED-PAT\/30158\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The sympathetic nervous system (SNS), particularly through the \u03b22 adrenergic receptor (\u03b22-AR), has been linked with breast cancer (BC) and the development of metastatic BC, specifically in the bone. Nevertheless, the potential clinical benefits of exploiting \u03b22-AR antagonists as a treatment for BC and bone loss-associated symptoms remain controversial. In this work, we show that, when compared to control individuals, the epinephrine levels in a cohort of BC patients are augmented in both earlier and late stages of the disease. Furthermore, through a combination of proteomic profiling and functional in vitro studies with human osteoclasts and osteoblasts, we demonstrate that paracrine signaling from parental BC under \u03b22-AR activation causes a robust decrease in human osteoclast differentiation and resorption activity, which is rescued in the presence of human osteoblasts. Conversely, metastatic bone tropic BC does not display this anti-osteoclastogenic effect. In conclusion, the observed changes in the proteomic profile of BC cells under \u03b2-AR activation that take place after metastatic dissemination, together with clinical data on epinephrine levels in BC patients, provided new insights on the sympathetic control of breast cancer and its implications on osteoclastic bone resorption.<\/jats:p>","DOI":"10.3390\/biom13040622","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T05:22:14Z","timestamp":1680153734000},"page":"622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Secretome of Parental and Bone Metastatic Breast Cancer Elicits Distinct Effects in Human Osteoclast Activity after Activation of \u03b22 Adrenergic Signaling"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4587-2470","authenticated-orcid":false,"given":"Francisco","family":"Concei\u00e7\u00e3o","sequence":"first","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8498-0664","authenticated-orcid":false,"given":"Daniela M.","family":"Sousa","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"given":"Sofia","family":"Tojal","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Catarina","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal"}]},{"given":"Carina","family":"Carvalho-Maia","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal"}]},{"given":"Helena","family":"Estev\u00e3o-Pereira","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-6694","authenticated-orcid":false,"given":"Marina","family":"Couto","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9600-3254","authenticated-orcid":false,"given":"Mette M.","family":"Rosenkilde","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal"}]},{"given":"Meriem","family":"Lamghari","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e000861","DOI":"10.1136\/esmoopen-2020-000861","article-title":"Breast Cancer: Global quality care optimizing care delivery with existing financial and personnel resources","volume":"4","author":"Verhoeven","year":"2019","journal-title":"ESMO Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100252","DOI":"10.1016\/j.jbo.2019.100252","article-title":"Denosumab for bone health in prostate and breast cancer patients receiving endocrine therapy? A systematic review and a meta-analysis of randomized trials","volume":"18","author":"Galvano","year":"2019","journal-title":"J. Bone Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1309\/AJCPYO5FSV3UPEXS","article-title":"Breast Cancer Subtypes Predispose the Site of Distant Metastases","volume":"143","author":"Soni","year":"2015","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrc3055","article-title":"Cancer to bone: A fatal attraction","volume":"11","author":"Weilbaecher","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1002\/jbmr.3618","article-title":"Understanding the Bone in Cancer Metastasis","volume":"33","author":"Fornetti","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jbo.2016.02.008","article-title":"The role of osteoclasts in breast cancer bone metastasis","volume":"5","author":"Vargas","year":"2016","journal-title":"J. Bone Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41572-020-00216-3","article-title":"Bone metastases","volume":"6","author":"Coleman","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Mehedin\u021beanu, A.M., Sfredel, V., Stovicek, P.O., Schenker, M., T\u00e2rtea, G.C., Istr\u0103toaie, O., Ciurea, A.-M., and Vere, C.C. (2021). Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042042"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bastos, D.B., Sarafim-Silva, B.A.M., Sundefeld, M.L.M.M., Ribeiro, A.A., Brand\u00e3o, J.D.P., Biasoli, \u00c9.R., Miyahara, G.I., Casarini, D.E., and Bernab\u00e9, D.G. (2018). Circulating catecholamines are associated with biobehavioral factors and anxiety symptoms in head and neck cancer patients. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202515"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1158\/1541-7786.MCR-17-0132","article-title":"Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow","volume":"15","author":"Decker","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Huang, Z., Li, G., Zhang, Z., Gu, R., Wang, W., Lai, X., Cui, Z.-K., Zeng, F., Xu, S., and Deng, F. (2019). \u03b22AR-HIF-1\u03b1-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6301-1"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1152\/physrev.00014.2017","article-title":"Impact of the Autonomic Nervous System on the Skeleton","volume":"98","author":"Elefteriou","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41413-021-00137-1","article-title":"Sympathetic activity in breast cancer and metastasis: Partners in crime","volume":"9","author":"Sousa","year":"2021","journal-title":"Bone Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Campbell, J.P., Karolak, M.R., Ma, Y., Perrien, D.S., Masood-Campbell, S.K., Penner, N.L., Munoz, S.A., Zijlstra, A., Yang, X., and Sterling, J.A. (2012). Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice. PLoS Biol., 10.","DOI":"10.1371\/journal.pbio.1001363"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41593-019-0430-3","article-title":"Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression","volume":"22","author":"Kamiya","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"628","DOI":"10.18632\/oncotarget.197","article-title":"Beta-Blocker Drug Therapy Reduces Secondary Cancer Formation in Breast Cancer and Improves Cancer Specific Survival","volume":"1","author":"Powe","year":"2010","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1200\/JCO.2010.33.4441","article-title":"Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer","volume":"29","author":"Lei","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s10549-013-2654-3","article-title":"Therapeutic effect of \u03b2-blockers in triple-negative breast cancer postmenopausal women","volume":"140","author":"Botteri","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1093\/ije\/dyt196","article-title":"Beta-blocker usage and breast cancer survival: A nested case\u2013control study within a UK Clinical Practice Research Datalink cohort","volume":"42","author":"Cardwell","year":"2014","journal-title":"Int. J. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13058-016-0782-5","article-title":"Propranolol and survival from breast cancer: A pooled analysis of European breast cancer cohorts","volume":"18","author":"Cardwell","year":"2016","journal-title":"Breast Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1200\/JCO.2012.43.9190","article-title":"Use of \u03b2-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study","volume":"31","author":"Ganz","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.clbc.2021.11.012","article-title":"Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early Stage Breast Cancer Patients: A Post hoc Analysis of the NCCTG-N9831 (Alliance) Trial","volume":"22","author":"Caparica","year":"2022","journal-title":"Clin. Breast Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"jcs229351","DOI":"10.1242\/jcs.229351","article-title":"Catabolic activity of osteoblast lineage cells contributes to osteoclastic bone resorption in vitro","volume":"132","author":"Pirapaharan","year":"2019","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1002\/jbmr.113","article-title":"Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle","volume":"25","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","article-title":"ilastik: Interactive machine learning for (bio)image analysis","volume":"16","author":"Berg","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"McQuin, C., Goodman, A., Chernyshev, V., Kamentsky, L., Cimini, B.A., Karhohs, K.W., Doan, M., Ding, L., Rafelski, S.M., and Thirstrup, D. (2018). CellProfiler 3.0: Next-generation image processing for biology. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005970"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s00223-012-9674-6","article-title":"Glucocorticoid-Induced Changes in the Geometry of Osteoclast Resorption Cavities Affect Trabecular Bone Stiffness","volume":"92","author":"Vanderoost","year":"2013","journal-title":"Calcif. Tissue Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15032","DOI":"10.1038\/boneres.2015.32","article-title":"Pit- and trench-forming osteoclasts: A distinction that matters","volume":"3","author":"Merrild","year":"2015","journal-title":"Bone Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9943","DOI":"10.1158\/0008-5472.CAN-05-0651","article-title":"Resveratrol Inhibits Myeloma Cell Growth, Prevents Osteoclast Formation, and Promotes Osteoblast Differentiation","volume":"65","author":"Boissy","year":"2005","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","article-title":"Single-pot, solid-phase-enhanced sample preparation for proteomics experiments","volume":"14","author":"Hughes","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Os\u00f3rio, H., Silva, C., Ferreira, M., Gullo, I., M\u00e1ximo, V., Barros, R., Mendon\u00e7a, F., Oliveira, C., and Carneiro, F. (2021). Proteomics Analysis of Gastric Cancer Patients with Diabetes Mellitus. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030407"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1535-6108(03)00132-6","article-title":"A multigenic program mediating breast cancer metastasis to bone","volume":"3","author":"Kang","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature14492","article-title":"The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase","volume":"522","author":"Cox","year":"2015","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1210\/en.2001-211424","article-title":"Stanniocalcin 1 Alters Muscle and Bone Structure and Function in Transgenic Mice","volume":"143","author":"Filvaroff","year":"2002","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bbrc.2014.05.074","article-title":"Secretory clusterin inhibits osteoclastogenesis by attenuating M-CSF-dependent osteoclast precursor cell proliferation","volume":"450","author":"Choi","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"647","DOI":"10.7150\/ijms.41075","article-title":"Connective tissue growth factor (CTGF) regulates the fusion of osteoclast precursors by inhibiting Bcl6 in periodontitis","volume":"17","author":"Choi","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"28696","DOI":"10.1016\/S0021-9258(19)61961-7","article-title":"Cloning and identification of annexin II as an autocrine\/paracrine factor that increases osteoclast formation and bone resorption","volume":"269","author":"Takahashi","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1242\/jcs.202036","article-title":"Time-lapse reveals that osteoclasts can move across the bone surface while resorbing","volume":"130","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5361","DOI":"10.1038\/s41598-019-41779-w","article-title":"Innervation is higher above Bone Remodeling Surfaces and in Cortical Pores in Human Bone: Lessons from patients with primary hyperparathyroidism","volume":"9","author":"Sayilekshmy","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1080\/10253890.2016.1203414","article-title":"Lipopolysaccharide induces catecholamine production in mesenteric adipose tissue of rats previously exposed to immobilization stress","volume":"19","author":"Vargovic","year":"2016","journal-title":"Stress"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1016\/j.febslet.2011.06.001","article-title":"Adipocytes as a new source of catecholamine production","volume":"585","author":"Vargovic","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e12752","DOI":"10.1111\/cpr.12752","article-title":"IGFBP7 acts as a negative regulator of RANKL-induced osteoclastogenesis and oestrogen deficiency-induced bone loss","volume":"53","author":"Ye","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.bone.2003.11.018","article-title":"Osteoclastogenesis is decreased by cysteine proteinase inhibitors","volume":"34","author":"Brage","year":"2004","journal-title":"Bone"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7042","DOI":"10.1158\/0008-5472.CAN-10-0522","article-title":"The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer","volume":"70","author":"Sloan","year":"2010","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10634","DOI":"10.1038\/ncomms10634","article-title":"Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination","volume":"7","author":"Le","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1038\/s41401-020-00509-z","article-title":"Quercetin prevents bone loss in hindlimb suspension mice via stanniocalcin 1-mediated inhibition of osteoclastogenesis","volume":"41","author":"Niu","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eabf2283","DOI":"10.1126\/sciadv.abf2283","article-title":"Breast cancer\u2013secreted factors perturb murine bone growth in regions prone to metastasis","volume":"7","author":"Chiou","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.7150\/thno.45351","article-title":"Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells","volume":"11","author":"Yuan","year":"2021","journal-title":"Theranostics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"17767","DOI":"10.1073\/pnas.1109402108","article-title":"Sympathetic control of bone mass regulated by osteopontin","volume":"108","author":"Nagao","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1084\/jem.20102608","article-title":"Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual","volume":"208","author":"Kajimura","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0167-4889(03)00042-9","article-title":"Effects of \u03b2-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells","volume":"1640","author":"Arai","year":"2003","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.bone.2008.03.026","article-title":"Osteoclast precursors acquire sensitivity to breast cancer derived factors early in differentiation","volume":"43","author":"Guo","year":"2008","journal-title":"Bone"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Aukes, K., Forsman, C., Brady, N.J., Astleford, K., Blixt, N., Sachdev, D., Jensen, E.D., Mansky, K.C., and Schwertfeger, K.L. (2017). Breast cancer cell-derived fibroblast growth factors enhance osteoclast activity and contribute to the formation of metastatic lesions. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185736"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s00223-018-0406-4","article-title":"Pharmacological Inhibition of the Skeletal IKK\u03b2 Reduces Breast Cancer-Induced Osteolysis","volume":"103","author":"Marino","year":"2018","journal-title":"Calcif. Tissue Int."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/ijc.20056","article-title":"Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte\/macrophage colony-stimulating factor","volume":"109","author":"Morgan","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.biochi.2014.07.017","article-title":"MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption","volume":"106","author":"He","year":"2014","journal-title":"Biochimie"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10549-006-9438-y","article-title":"RANKL-dependent and RANKL-independent mechanisms of macrophage-osteoclast differentiation in breast cancer","volume":"105","author":"Lau","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.abb.2008.11.012","article-title":"\u03b22-Adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms","volume":"482","author":"Aitken","year":"2009","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E507","DOI":"10.1152\/ajpendo.00191.2012","article-title":"\u03b2-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species","volume":"304","author":"Kondo","year":"2013","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Mukaida, N., Zhang, D., and Sasaki, S.-i. (2020). Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process. Cancers, 12.","DOI":"10.3390\/cancers12102896"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jbo.2018.09.002","article-title":"\u03b22ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1\u03b2 and selectin-dependent manner","volume":"13","author":"Mulcrone","year":"2018","journal-title":"J. Bone Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Karavitis, J., Hix, L.M., Shi, Y.H., Schultz, R.F., Khazaie, K., and Zhang, M. (2012). Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046342"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.bbrc.2016.11.011","article-title":"Beta-adrenergic signaling affect osteoclastogenesis via osteocytic MLO-Y4 cells\u2019 RANKL production","volume":"488","author":"Yao","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1038\/cr.2012.90","article-title":"Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis","volume":"22","author":"Jin","year":"2012","journal-title":"Cell Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/path.5197","article-title":"Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer","volume":"247","author":"Westbrook","year":"2019","journal-title":"J. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Gruet, M., Cotton, D., Coveney, C., Boocock, D.J., Wagner, S., Komorowski, L., Rees, R.C., Pockley, A.G., Garner, A.C., and Wallis, J.D. (2020). \u03b22-Adrenergic Signalling Promotes Cell Migration by Upregulating Expression of the Metastasis-Associated Molecule LYPD3. Biology, 9.","DOI":"10.3390\/biology9020039"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"12682","DOI":"10.18632\/oncotarget.3707","article-title":"Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells","volume":"6","author":"Burnett","year":"2015","journal-title":"Oncotarget"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41586-019-1576-6","article-title":"Synaptic proximity enables NMDAR signalling to promote brain metastasis","volume":"573","author":"Zeng","year":"2019","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1096\/fj.15-277798","article-title":"The \u03b22-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion","volume":"30","author":"Pon","year":"2016","journal-title":"FASEB J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1111\/bcp.14030","article-title":"Prognostic significance of \u03b1- and \u03b22-adrenoceptor gene expression in breast cancer patients","volume":"85","author":"Rivero","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1185\/03007995.2014.890928","article-title":"Association of alpha2a and beta2 adrenoceptor expression with clinical outcome in breast cancer","volume":"30","author":"Du","year":"2014","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Sousa, D.M., Fernandes, V., Louren\u00e7o, C., Carvalho-Maia, C., Estev\u00e3o-Pereira, H., Lobo, J., Cantante, M., Couto, M., Concei\u00e7\u00e3o, F., and Jer\u00f3nimo, C. (2022). Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis. Cancers, 14.","DOI":"10.3390\/cancers14225518"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/ajh\/4.8.709","article-title":"Acute Effects of Combined \u03b1\/\u03b2-Adrenoceptor Blockade \u03c5 Combined \u03b2-Receptor and Slow Channel Calcium Blockade in Ischemic Heart Disease Complicated by Hypertension: Hemodynamic and Adrenergic Responses","volume":"4","author":"Koch","year":"1991","journal-title":"Am. J. Hypertens."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/npp.1993.18","article-title":"Effects of Acute and Chronic Alprazolam Treatment on Cerebral Blood Flow, Memory, Sedation, and Plasma Catecholamines","volume":"8","author":"Fleishaker","year":"1993","journal-title":"Neuropsychopharmacology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e005465","DOI":"10.1161\/JAHA.116.005465","article-title":"Cigarette Smoking-Associated Alterations in Serotonin\/Adrenalin Signaling Pathways of Platelets","volume":"6","author":"Lowery","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/sj.jhh.1002288","article-title":"Sympathoadrenergic and metabolic factors are involved in ambulatory blood pressure rise in childhood obesity","volume":"22","author":"Gilardini","year":"2008","journal-title":"J. Hum. Hypertens."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1177\/0271678X19842680","article-title":"Hypoglycemic thalamic activation in type 1 diabetes is associated with preserved symptoms despite reduced epinephrine","volume":"40","author":"Nwokolo","year":"2020","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_80","first-page":"D442","article-title":"The PRIDE database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Csordas","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:07:03Z","timestamp":1760123223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":80,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["biom13040622"],"URL":"https:\/\/doi.org\/10.3390\/biom13040622","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]}}}