Sympathetic activity in breast cancer and metastasis: partners in crime

Abstract

The vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

References

[1] Lyons CE et al. Optogenetic-induced sympathetic neuromodulation of brown adipose tissue thermogenesis. FASEB J., 2020, 34: 2765-2773

[2] Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer, 2015, 15: 563-572

[3] Katayama Y et al. Signals from the sympathetic nervous system regulate hematopoietic stem. Cell Egr. Bone Marrow Cell, 2006, 124: 407-421

[4] Mani BK, Osborne-Lawrence S, Vijayaraghavan P, Hepler C, Zigman JM. β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals. J. Clin. Investig., 2016, 126: 3467-3478

[5] Arai M, Nagasawa T, Koshihara Y, Yamamoto S, Togari A. Effects of β-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells. Biochim. Biophys. Acta (BBA)—Mol. Cell Res., 2003, 1640: 137-142

[6] Huang HH, Brennan TC, Muir MM, Mason RS. Functional α1- and β2-adrenergic receptors in human osteoblasts. J. Cell Physiol., 2009, 220: 267-275

[7] Wu L et al. Bidirectional role of β2-adrenergic receptor in autoimmune diseases. Front. Pharmacol., 2018, 9: 1313

[8] Ali DC et al. β-Adrenergic receptor, an essential target in cardiovascular diseases. Heart Fail. Rev., 2020, 25: 343-354

[9] Galvano A et al. Denosumab for bone health in prostate and breast cancer patients receiving endocrine therapy? A systematic review and a meta-analysis of randomized trials. J. Bone Oncol., 2019, 18: 100252

[10] Powe DG et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget, 2010, 1: 628-638

[11] Campbell JP et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLOS Biol., 2012, 10

[12] Obradović MMS et al. Glucocorticoids promote breast cancer metastasis. Nature, 2019, 567: 540-544

[13] Perron L, Bairati I, Harel F, Meyer F. Antihypertensive drug use and the risk of prostate cancer (Canada). Cancer Causes Control CCC, 2004, 15: 535-541

[14] Hassan S et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Investig., 2013, 123: 874-886

[15] Magnon C et al. Autonomic nerve development contributes to prostate cancer progression. Science, 2013, 341: 1236361

[16] Decker AM et al. Sympathetic signaling reactivates quiescent disseminated prostate cancer cells in the bone marrow. Mol. Cancer Res., 2017, 15: 1644-1655

[17] Coarfa C et al. Influence of the neural microenvironment on prostate cancer. Prostate, 2018, 78: 128-139

[18] Jimenez-Andrade JM et al. Bone cancer pain. Ann. N. Y. Acad. Sci., 2010, 1198: 173-181

[19] Liu D et al. A Her2-let-7-β2-AR circuit affects prognosis in patients with Her2-positive breast cancer. BMC Cancer, 2015, 15

[20] Rivero EM et al. Prognostic significance of α- and β2-adrenoceptor gene expression in breast cancer patients. Br. J. Clin. Pharmacol., 2019, 85: 2143-2154

[21] Kurozumi S et al. β2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer. Breast Cancer Res. Treat., 2019, 177: 603-610

[22] Hanahan D, Weinberg RobertA. Hallmarks of cancer: the next generation. Cell, 2011, 144: 646-674

[23] Pérez Piñero C, Bruzzone A, Sarappa M, Castillo L, Lüthy I. Involvement of α2- and β2-adrenoceptors on breast cancer cell proliferation and tumour growth regulation. Br. J. Pharmacol., 2012, 166: 721-736

[24] Sastry KSR et al. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J. Biol. Chem., 2007, 282: 14094-14100

[25] Reeder A et al. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage. Br. J. Cancer, 2015, 112: 1461-1470

[26] Slotkin TA et al. β-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells. Breast Cancer Res. Treat., 2000, 60: 153-166

[27] Gargiulo L et al. Differential á2-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines. Oncotarget, 2014, 5: 10058-10069

[28] Walker AK et al. Circulating epinephrine is not required for chronic stress to enhance metastasis. Psychoneuroendocrinology, 2019, 99: 191-195

[29] Le CP et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat. Commun., 2016, 7

[30] Sloan EK et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res., 2010, 70: 7042-7052

[31] Bruzzone A et al. α2-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. Curr. Cancer Drug Targets, 2011, 11: 763-774

[32] Thaker PH et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med., 2006, 12: 939-944

[33] Lamkin DM et al. 2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology, 2015, 51: 262-270

[34] Kamiya A et al. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat. Neurosci., 2019, 22: 1289-1305

[35] Hein L, Altman JD, Kobilka BK. Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission. Nature, 1999, 402: 181-184

[36] Nagy JA, Chang S-H, Shih S-C, Dvorak AM, Dvorak HF. Heterogeneity of the Tumor Vasculature. Semin Thromb. Hemost., 2010, 36: 321-331

[37] Madden KS, Szpunar MJ, Brown EB. β-Adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines. Breast Cancer Res. Treat., 2011, 130: 747-758

[38] Chen H et al. Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk. Endocr Relat Cancer, 2014, 21: 783-795

[39] Zhou J et al. Activation of β2-adrenergic receptor promotes growth and angiogenesis in breast cancer by down-regulating PPARγ. Cancer Res. Treat., 2020, 52: 830-847

[40] Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol., 2006, 6: 318-328

[41] Hanoun M, Maryanovich M, Arnal-Estapé A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron, 2015, 86: 360-373

[42] Szpunar MJ, Belcher EK, Dawes RP, Madden KS. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer. Brain Behav. Immun., 2016, 53: 223-233

[43] Lamkin DM et al. β-Adrenergic-stimulated macrophages: comprehensive localization in the M1-M2 spectrum. Brain, Behav., Immun., 2016, 57: 338-346

[44] Bucsek MJ et al. β-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8⁺ T cells and undermines checkpoint inhibitor therapy. Cancer Res., 2017, 77: 5639-5651

[45] Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: correlation or causality? FEBS Lett., 2015, 589: 1577-1587

[46] Chang A et al. β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav. Immun., 2016, 57: 106-115

[47] Pon CK, Lane JR, Sloan EK, Halls ML. The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. FASEB J., 2016, 30: 1144-1154

[48] Creed SJ et al. β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Res., 2015, 17

[49] Kim T-H et al. Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling. J. Cell Sci., 2016, 129: 4563-4575

[50] Dezong G, Zhongbing M, Qinye F, Zhigang Y. Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. J. Cancer Res. Ther., 2014, 10: 991-997

[51] Szpunar MJ, Burke KA, Dawes RP, Brown EB, Madden KS. The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev. Res., 2013, 6: 1262-1272

[52] Soni A et al. Breast cancer subtypes predispose the site of distant metastases. Am. J. Clin. Pathol., 2015, 143: 471-478

[53] Ignatov A, Eggemann H, Burger E, Ignatov T. Patterns of breast cancer relapse in accordance to biological subtype. J. Cancer Res. Clin. Oncol., 2018, 144: 1347-1355

[54] Yang H et al. Impact of molecular subtypes on metastatic behavior and overall survival in patients with metastatic breast cancer: a single-center study combined with a large cohort study based on the surveillance, epidemiology and end results database. Oncol. Lett., 2020, 20: 87

[55] Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat. Rev. Cancer, 2011, 11: 411-425

[56] Fornetti J, Welm AL, Stewart SA. Understanding the bone in cancer metastasis. J. Bone Miner. Res., 2018, 33: 2099-2113

[57] Kang Y. Dissecting tumor-stromal interactions in breast cancer bone metastasis. Endocrinol. Metab., 2016, 31: 206-212

[58] Drake FH et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J. Biol. Chem., 1996, 271: 12511-12516

[59] Halleen JM et al. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J. Bone Miner. Res., 2000, 15: 1337-1345

[60] Ecarot-Charrier B, Glorieux FH, van der Rest M, Pereira G. Osteoblasts isolated from mouse calvaria initiate matrix mineralization in culture. J. Cell Biol., 1983, 96: 639-643

[61] Kamioka H, Honjo T, Takano-Yamamoto T. A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy. Bone, 2001, 28: 145-149

[62] Feng JQ et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet., 2006, 38: 1310-1315

[63] Robling AG et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/sclerostin. J. Biol. Chem., 2008, 283: 5866-5875

[64] Kamel MA, Picconi JL, Lara-Castillo N, Johnson ML. Activation of β-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: implications for the study of mechanosensation in bone. Bone, 2010, 47: 872-881

[65] Yin JJ et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Investig., 1999, 103: 197-206

[66] Le Pape F, Vargas G, Clézardin P. The role of osteoclasts in breast cancer bone metastasis. J. Bone Oncol., 2016, 5: 93-95

[67] Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer, 2002, 2: 584-593

[68] Fizazi K 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] Chartier SR, Mitchell SAT, Majuta LA, Mantyh PW. The changing sensory and sympathetic innervation of the young, adult and aging mouse femur. Neuroscience, 2018, 387: 178-190

[70] Leitão L et al. Osteoblasts are inherently programmed to repel sensory innervation. Bone Res., 2020, 8: 20

[71] Sayilekshmy M et al. Innervation is higher above bone remodeling surfaces and in cortical pores in human bone: lessons from patients with primary hyperparathyroidism. Sci. Rep., 2019, 9

[72] Fonseca TL et al. Double disruption of α2A- and α2C -adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype. J. Bone Miner. Res., 2011, 26: 591-603

[73] Nishiura T, Abe K. α1-Adrenergic receptor stimulation induces the expression of receptor activator of nuclear factor κB ligand gene via protein kinase C and extracellular signal-regulated kinase pathways in MC3T3-E1 osteoblast-like cells. Arch. Oral. Biol., 2007, 52: 778-785

[74] Hirai T, Tanaka K, Togari A. α1-adrenergic receptor signaling in osteoblasts regulates clock genes and bone morphogenetic protein 4 expression through up-regulation of the transcriptional factor nuclear factor IL-3 (Nfil3)/E4 promoter-binding protein 4 (E4BP4). J. Biol. Chem., 2014, 289: 17174-17183

[75] Kondo H, Takeuchi S, Togari A. β-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species. Am. J. Physiol.-Endocrinol. Metab., 2013, 304: E507-E515

[76] Moore RE, Smith CK, Bailey CS, Voelkel EF, Tashjian AH. Characterization of beta-adrenergic receptors on rat and human osteoblast-like cells and demonstration that beta-receptor agonists can stimulate bone resorption in organ culture. Bone Miner., 1993, 23: 301-315

[77] Takeda S et al. Leptin regulates bone formation via the sympathetic nervous system. Cell, 2002, 111: 305-317

[78] Togari A et al. Expression of mRNAs for neuropeptide receptors and β-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. Neurosci. Lett., 1997, 233: 125-128

[79] Aitken SJ, Landao-Bassonga E, Ralston SH, Idris AI. β2-Adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Arch. Biochem. Biophysics, 2009, 482: 96-103

[80] Ma Y et al. Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis. J. Biol. Chem., 2013, 288: 30105-30113

[81] Elefteriou F. Impact of the autonomic nervous system on the skeleton. Physiol. Rev., 2018, 98: 1083-1112

[82] Elefteriou F et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature, 2005, 434: 514-520

[83] Liang H et al. Selective β2-adrenoreceptor signaling regulates osteoclastogenesis via modulating RANKL production and neuropeptides expression in osteocytic MLO-Y4 cells. J. Cell. Biochem., 2019, 120: 7238-7247

[84] Yao Q et al. Beta-adrenergic signaling affect osteoclastogenesis via osteocytic MLO-Y4 cells’ RANKL production. Biochem. Biophysi. Res. Commun., 2017, 488: 634-640

[85] Chen A et al. Attraction and compaction of migratory breast cancer cells by bone matrix proteins through tumor-osteocyte interactions. Sci. Rep., 2018, 8

[86] Liu S et al. Osteocyte-driven downregulation of snail restrains effects of Drd2 inhibitors on mammary tumor cells. Cancer Res., 2018, 78: 3865-3876

[87] Fan Y et al. Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion. Bone Res., 2020, 8: 9

[88] Maroni P, Bendinelli P. Bone, a secondary growth site of breast and prostate carcinomas: role of osteocytes. Cancers, 2020, 12: 1812

[89] Mulcrone PL et al. Skeletal colonization by breast cancer cells is stimulated by an osteoblast and β2AR-dependent neo-angiogenic switch. J. Bone Miner. Res., 2017, 32: 1442-1454

[90] Clément-Demange L, Mulcrone PL, Tabarestani TQ, Sterling JA, Elefteriou F. β2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1β and selectin-dependent manner. J. Bone Oncol., 2018, 13: 1-10

[91] Martin, T. J. & Johnson, R. W. Multiple actions of parathyroid hormone-related protein in breast cancer bone metastasis. Br. J. Pharmacol. 1–13 (2019). https://doi.org/10.1111/bph.14709. Online ahead of print.

[92] Thomas RJ et al. Breast cancer cells interact with osteoblasts to support osteoclast formation1. Endocrinology, 1999, 140: 4451-4458

[93] Hanyu R et al. Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor. Proc. Natl Acad. Sci., 2012, 109: 7433-7438

[94] Moriya S et al. PTH regulates β2-adrenergic receptor expression in osteoblast-Like MC3T3-E1 cells. J. Cell. Biochem., 2015, 116: 142-148

[95] Bianchi EN, Ferrari SL. β-arrestin2 regulates parathyroid hormone effects on a p38 MAPK and NFκB gene expression network in osteoblasts. Bone, 2009, 45: 716-725

[96] Spurney RF. Regulated expression of G protein-coupled receptor kinases (GRK’s) and β-arrestins in osteoblasts. Calcif. Tissue Int., 2003, 73: 153-160

[97] Fukayama S, Kong G, Benovic JL, Meurer E. & Jr, A. H. T. β-adrenergic receptor kinase-1 acutely regulates PTH/PTHrP receptor signalling in human osteoblastlike cells. Cell. Signal., 1997, 9: 469-474

[98] Gesty-Palmer D et al. Distinct β-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 Activation. J. Biol. Chem., 2006, 281: 10856-10864

[99] Cardwell CR et al. Propranolol and survival from breast cancer: a pooled analysis of European breast cancer cohorts. Breast Cancer Res., 2016, 18

[100] Chida Y, Hamer M, Wardle J, Steptoe A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol., 2008, 5: 466-475

[101] Lawrence DS, Sahay JN, Chatterjee SS, Cruickshank JM. Asthma and beta-blockers. Eur. J. Clin. Pharmacol., 1982, 22: 501-509

[102] Paterson JW, Dollery CT. Effect of propranolol in MILD hypertension. Lancet, 1966, 288: 1148-1150

[103] Fryzek JP et al. A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res. Treat., 2006, 97: 231-236

[104] Li CI et al. Relation between use of antihypertensive medications and risk of breast carcinoma among women ages 65–79 years. Cancer, 2003, 98: 1504-1513

[105] Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J. Clin. Oncol., 2011, 29: 2635-2644

[106] Melhem-Bertrandt A et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol., 2011, 29: 2645-2652

[107] Montoya A et al. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer. Oncotarget, 2016, 8: 6446-6460

[108] Botteri E et al. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res. Treat., 2013, 140: 567-575

[109] Spera G et al. Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study. Ann. Oncol., 2017, 28: 1836-1841

[110] Shah SM et al. Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br. J. Clin. Pharmacol., 2011, 72: 157-161

[111] Sørensen GV et al. Use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. J. Clin. Oncol., 2013, 31: 2265-2272

[112] Cardwell CR, Coleman HG, Murray LJ, Entschladen F, Powe DG. Beta-blocker usage and breast cancer survival: a nested case-control study within a UK Clinical Practice Research Datalink cohort. Int. J. Epidemiol., 2014, 42: 1852-1861

[113] Zhou L et al. Propranolol attenuates surgical stress–induced elevation of the regulatory Tt cell response in patients undergoing radical mastectomy. J. Immunol., 2016, 196: 3460-3469

[114] Shaashua L et al. Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin. Cancer Res., 2017, 23: 4651-4661

[115] Haldar R et al. Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav. Immun., 2018, 73: 294-309

[116] Hiller JG et al. Pre-operative β-blockade with propranolol reduces biomarkers of metastasis in breast cancer: a Phase II randomized trial. Clin. Cancer Res., 2020, 26: 1803-1811

[117] Lechtenberg KJ, Meyer ST, Doyle JB, Peterson TC, Buckwalter MS. Augmented β2-adrenergic signaling dampens the neuroinflammatory response following ischemic stroke and increases stroke size. J. Neuroinflammation, 2019, 16

[118] Mei X et al. Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis. Integr. Biol., 2019, 11: 119-129

[119] Hao S et al. A Spontaneous 3D bone-on-a-chip for bone metastasis study of breast cancer cells. Small, 2018, 14: 1702787

[120] Bersini S et al. A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials, 2014, 35: 2454-2461

[121] Jeon JS et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc. Natl Acad. Sci. USA, 2015, 112: 214-219

[122] Dubový P et al. Local chemical sympathectomy of rat bone marrow and its effect on marrow cell composition. Autonom. Neurosci.: basic Clin., 2017, 206: 19-27

[123] Wu H, Luo Y, Xu D, Ke X, Ci T. Low molecular weight heparin modified bone targeting liposomes for orthotopic osteosarcoma and breast cancer bone metastatic tumors. Int. J. Biol. Macromolecules, 2020, 164: 2583-2597

[124] Jiang B et al. Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation. Drug Deliv., 2012, 19: 317-326

[125] Zhang G et al. A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy. Nat. Med., 2012, 18: 307-314

[126] Salerno M et al. Bone-targeted doxorubicin-loaded nanoparticles as a tool for the treatment of skeletal metastases. Curr. Cancer Drug Targets, 2010, 10: 649-659

[127] Wang C et al. Trifolium-like platinum nanoparticle-mediated photothermal therapy inhibits tumor growth and osteolysis in a bone metastasis model. Small, 2015, 11: 2080-2086

[128] Wang X et al. Peptide decoration of nanovehicles to achieve active targeting and pathology-responsive cellular uptake for bone metastasis chemotherapy. Biomater. Sci., 2014, 2: 961-971

[129] Kievit FM et al. Targeting of primary breast cancers and metastases in a transgenic mouse model using rationally designed multifunctional SPIONs. ACS Nano, 2012, 6: 2591-2601

[130] Castillo LF, Rivero EM, Goffin V, Lüthy IA. Alpha2-adrenoceptor agonists trigger prolactin signaling in breast cancer cells. Cell. Signal., 2017, 34: 76-85

[131] Cakir Y, Plummer HK, Tithof PK, Schuller HM. Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int. J. Oncol., 2002, 21: 153-157

[132] Vázquez SM et al. Human breast cell lines exhibit functional α2-adrenoceptors. Cancer Chemother. Pharmacol., 2005, 58: 50-61

[133] Strell C et al. Norepinephrine promotes the β1-integrin–mediated adhesion of MDA-MB-231 cells to vascular endothelium by the induction of a GROα release. Mol. Cancer Res., 2012, 10: 197-207

[134] Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW. Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res. Treat., 2011, 129: 549-556

Funding

FCT - Fundação para a Ciência e a Tecnologia; Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES). Grant Reference Number - POCI-01-0145-FEDER-030158; PTDC/MED-PAT/30158/2017

FCT - Fundação para a Ciência e a Tecnologia; Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES). Grant Reference Number - SFRH/BD/128771/2017

FCT - Fundação para a Ciência e a Tecnologia; Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES). Grant Reference Number - SFRH/BPD/115341/2016