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Breast cancer at bone metastatic sites: recent discoveries and treatment targets

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  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Breast carcinoma is the most common cancer of women. Bones are often involved with breast carcinoma metastases with the resulting morbidity and reduced quality of life. Breast cancer cells arriving at bone tissues mount supportive microenvironment by recruiting and modulating the activity of several host tissue cell types including the specialized bone cells osteoblasts and osteoclasts. Pathologically activated osteoclasts produce osteolytic lesions associated with bone pain, pathological fractures, cord compression and other complications of metastatic breast carcinoma at bone. Over the last decade there has been enormous growth of knowledge in the field of osteoclasts biology both in the physiological state and in the tumor microenvironment. This knowledge allowed the development and implementation of several targeted therapeutics that expanded the armamentarium of the oncologists dealing with the metastases-associated osteolytic disease. While the interactions of cancer cells with resident bone cells at the established metastatic gross lesions are well-studied, the preclinical events that underlie the progression of disseminated tumor cells into micrometastases and then into clinically-overt macrometastases are just starting to be uncovered. In this review, we discuss the established information and the most recent discoveries in the pathogenesis of osteolytic metastases of breast cancer, as well as the corresponding investigational drugs that have been introduced into clinical development.

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Abbreviations

BCC:

Breast Carcinoma Cells

BIM:

Bcl-2-interacting mediator of cell death

CSC:

Cancer Stem Cells

DTC:

Disseminated Tumor Cells

EMT:

Epithelial-Mesenchymal-Transition

ER:

Estrogen Receptors

GPNMB:

Glycoprotein Non-Metastatic B

HER2:

Human Epidermal growth factor Receptor 2

HSC:

Hematopoietic Stem Cells

ITAM:

Immunoreceptor Tyrosine-based Activation Motifs

MBCC:

Metastatic Breast Carcinoma Cells

MCSF:

Macrophage Colony Stimulating Factor

MSC:

Mesenchymal Stem Cells

mTOR:

mammalian Target Of Rapamycin

NBP:

Nitrogen-containing Bisphosphonates

NFAT:

Nuclear Factor of Activated T cell

OPG:

Osteoprotegerin

PTHrP:

Parathyroid Hormone related Protein

RANKL:

Receptor Activator of Nuclear factor κB Ligand

SRE:

Skeletal-Related Events

SRS:

Src Responsive Signature

TRAIL:

TNF-Related Apoptosis Inducing Ligand

ZA:

Zoledronic acid

References

  • Abraham BK, Fritz P et al (2005) Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11(3):1154–1159

    PubMed  CAS  Google Scholar 

  • Aft R, Naughton M et al (2010) Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 11(5):421–428

    PubMed  CAS  Google Scholar 

  • Aguirre-Ghiso JA, Liu D et al (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12(4):863–879

    PubMed  CAS  Google Scholar 

  • Aicher A, Kollet O et al (2008) The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche. Circ Res 103(8):796–803

    PubMed  CAS  Google Scholar 

  • Akhtari M, Mansuri J et al (2008) Biology of breast cancer bone metastasis. Cancer Biol Ther 7(1):3–9

    PubMed  CAS  Google Scholar 

  • Al-Hajj M, Wicha MS et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    PubMed  CAS  Google Scholar 

  • Aliprantis AO, Ueki Y et al (2008) NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest 118(11):3775–3789

    PubMed  CAS  Google Scholar 

  • Andre F, Xia W et al (2009) CXCR4 expression in early breast cancer and risk of distant recurrence. Oncologist 14(12):1182–1188

    PubMed  CAS  Google Scholar 

  • Araujo J, Logothetis C (2009) Targeting Src signaling in metastatic bone disease. Int J Cancer 124(1):1–6

    PubMed  CAS  Google Scholar 

  • Araujo J, Logothetis C (2010) Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors. Cancer Treat Rev 36(6):492–500

    PubMed  CAS  Google Scholar 

  • Araujo JC, Poblenz A et al (2009) Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation. Cancer Biol Ther 8(22):2153–2159

    PubMed  CAS  Google Scholar 

  • Armstrong AP, Miller RE et al (2008) RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 68(1):92–104

    PubMed  CAS  Google Scholar 

  • Balic M, Lin H et al (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621

    PubMed  CAS  Google Scholar 

  • Barkan D, Kleinman H et al (2008) Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res 68(15):6241–6250

    PubMed  CAS  Google Scholar 

  • Barkan D, El Touny LH et al (2010) Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res 70(14):5706–5716

    PubMed  CAS  Google Scholar 

  • Barrios J, Wieder R (2009) Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy. Cancer Microenviron 2(1):33–47

    PubMed  Google Scholar 

  • Bendre MS, Gaddy-Kurten D et al (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62(19):5571–5579

    PubMed  CAS  Google Scholar 

  • Bendre M, Gaddy D, et al (2003a) Breast cancer metastasis to bone: it is not all about PTHrP. Clin Orthop Relat Res (415 Suppl):S39–S45

  • Bendre MS, Montague DC et al (2003b) Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 33(1):28–37

    PubMed  CAS  Google Scholar 

  • Bendre MS, Margulies AG et al (2005) Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 65(23):11001–11009

    PubMed  CAS  Google Scholar 

  • Berenson JR, Rajdev L et al (2006) Pathophysiology of bone metastases. Cancer Biol Ther 5(9):1078–1081

    PubMed  Google Scholar 

  • Berry DA, Cronin KA et al (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353(17):1784–1792

    PubMed  CAS  Google Scholar 

  • Bidard FC, Vincent-Salomon A et al (2008) Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 14(11):3306–3311

    PubMed  CAS  Google Scholar 

  • Bierie B, Chung CH et al (2009) Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 119(6):1571–1582

    PubMed  CAS  Google Scholar 

  • Blair HC, Athanasou NA (2004) Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 19(1):189–199

    PubMed  CAS  Google Scholar 

  • Body JJ, Facon T et al (2006) 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 12(4):1221–1228

    PubMed  CAS  Google Scholar 

  • Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473(2):139–146

    PubMed  CAS  Google Scholar 

  • Brouard N, Driessen R et al (2010) G-CSF increases mesenchymal precursor cell numbers in the bone marrow via an indirect mechanism involving osteoclast-mediated bone resorption. Stem Cell Res 5(1):65–75

    PubMed  CAS  Google Scholar 

  • Brufsky A, Harker WG et al (2007) Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25(7):829–836

    PubMed  CAS  Google Scholar 

  • Brufsky A, Bundred N et al (2008) Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13(5):503–514

    PubMed  CAS  Google Scholar 

  • Brufsky AM, Bosserman LD et al (2009) Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 9(2):77–85

    PubMed  CAS  Google Scholar 

  • Bundred NJ, Campbell ID et al (2008) Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer 112(5):1001–1010

    PubMed  CAS  Google Scholar 

  • Cabioglu N, Sahin AA et al (2009) Chemokine receptors in advanced breast cancer: differential expression in metastatic disease sites with diagnostic and therapeutic implications. Ann Oncol 20(6):1013–1019

    PubMed  CAS  Google Scholar 

  • Calvi LM, Adams GB et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846

    PubMed  CAS  Google Scholar 

  • Carteni G, Bordonaro R et al (2006) Efficacy and safety of zoledronic acid in patients with breast cancer metastatic to bone: a multicenter clinical trial. Oncologist 11(7):841–848

    PubMed  CAS  Google Scholar 

  • Casimiro S, Guise TA et al (2009) The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol 310(1–2):71–81

    PubMed  CAS  Google Scholar 

  • Chatterjee M, van Golen KL (2010) Farnesyl transferase inhibitor treatment of breast cancer cells leads to altered RhoA and RhoC GTPase activity and induces a dormant phenotype. Int J Cancer

  • Chen YC, Sosnoski DM et al (2009) Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer. Carcinogenesis 30(11):1941–1948

    PubMed  CAS  Google Scholar 

  • Chiedozi LC (1988) Prognostic significance of exclusive skeletal metastases in stage IV primary carcinoma of the breast. Surg Gynecol Obstet 167(4):303–306

    PubMed  CAS  Google Scholar 

  • Chirgwin JM, Guise TA (2000) Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr 10(2):159–178

    PubMed  CAS  Google Scholar 

  • Cho SY, Choi HY (1980) Causes of death and metastatic patterns in patients with mammary cancer. Ten-year autopsy study. Am J Clin Pathol 73(2):232–234

    PubMed  CAS  Google Scholar 

  • Cho KA, Joo SY et al (2010) Osteoclast activation by receptor activator of NF-kappaB ligand enhances the mobilization of hematopoietic progenitor cells from the bone marrow in acute injury. Int J Mol Med 26(4):557–563

    PubMed  CAS  Google Scholar 

  • Cifuentes N, Pickren JW (1979) Metastases from carcinoma of mammary gland: an autopsy study. J Surg Oncol 11(3):193–205

    PubMed  CAS  Google Scholar 

  • Clezardin P, Teti A (2007) Bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis 24(8):599–608

    PubMed  CAS  Google Scholar 

  • Clines GA, Guise TA (2005) Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 12(3):549–583

    PubMed  CAS  Google Scholar 

  • Clines GA, Guise TA (2008) Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 10:e7

    PubMed  Google Scholar 

  • Creighton CJ, Chang JC et al (2010) Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 15(2):253–260

    PubMed  Google Scholar 

  • Croker AK, Allan AL (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 12(2):374–390

    PubMed  CAS  Google Scholar 

  • Dai XM, Ryan GR et al (2002) Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99(1):111–120

    PubMed  CAS  Google Scholar 

  • Dai J, Lu Y et al (2010) Reversal of chemotherapy-induced leukopenia using granulocyte macrophage colony-stimulating factor promotes bone metastasis that can be blocked with osteoclast inhibitors. Cancer Res 70(12):5014–5023

    PubMed  CAS  Google Scholar 

  • Danen EH, Sonneveld P et al (2002) The fibronectin-binding integrins alpha5beta1 and alphavbeta3 differentially modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis. J Cell Biol 159(6):1071–1086

    PubMed  CAS  Google Scholar 

  • Denoyelle C, Hong L et al (2003) New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. Br J Cancer 88(10):1631–1640

    PubMed  CAS  Google Scholar 

  • Diel IJ, Jaschke A et al (2008) Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 19(12):2007–2011

    PubMed  CAS  Google Scholar 

  • Dieli F, Vermijlen D et al (2007) Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67(15):7450–7457

    PubMed  CAS  Google Scholar 

  • Dougall WC, Glaccum M et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13(18):2412–2424

    PubMed  CAS  Google Scholar 

  • Facchini G, Caraglia M et al (2007) The clinical response on bone metastasis from breast and lung cancer during treatment with zoledronic acid is inversely correlated to skeletal related events (SRE). J Exp Clin Cancer Res 26(3):307–312

    PubMed  CAS  Google Scholar 

  • Fehm T, Beck V et al (2009) Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 112(3):605–609

    PubMed  CAS  Google Scholar 

  • Ferlay J, Héry C, et al (2010) Global burden of breast cancer. Breast Cancer Epidemiology. C. Li, Springer New York, 1–19

  • Finn RS, Dering J et al (2007) Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat 105(3):319–326

    PubMed  CAS  Google Scholar 

  • Fisher JL, Thomas-Mudge RJ et al (2006) Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res 66(7):3620–3628

    PubMed  CAS  Google Scholar 

  • Fizazi K, Lipton A et al (2009) 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 27(10):1564–1571

    PubMed  CAS  Google Scholar 

  • Foekens JA, Atkins D et al (2006) Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24(11):1665–1671

    PubMed  CAS  Google Scholar 

  • Fong JE, Le Nihouannen D et al (2010) Tumor-supportive and osteoclastogenic changes induced by breast cancer-derived factors are reversed by inhibition of {gamma}-secretase. J Biol Chem 285(41):31427–31434

    PubMed  CAS  Google Scholar 

  • Gallet M, Sevenet N et al (2004) Breast cancer cell line MDA-MB 231 exerts a potent and direct anti-apoptotic effect on mature osteoclasts. Biochem Biophys Res Commun 319(2):690–696

    PubMed  CAS  Google Scholar 

  • Gallet M, Mentaverri R et al (2006) Ability of breast cancer cell lines to stimulate bone resorbing activity of mature osteoclasts correlates with an anti-apoptotic effect mediated by macrophage colony stimulating factor. Apoptosis 11(11):1909–1921

    PubMed  CAS  Google Scholar 

  • Gatien M, Benjamin O et al (2010) Therapeutic approach of primary bone tumours by bisphosphonates. Curr Pharm Des 16(27):2981–2987

    Google Scholar 

  • Gnant MF, Mlineritsch B et al (2007) Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25(7):820–828

    PubMed  CAS  Google Scholar 

  • Gnant M, Mlineritsch B et al (2008) Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 9(9):840–849

    PubMed  CAS  Google Scholar 

  • Gnant M, Mlineritsch B et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360(7):679–691

    PubMed  CAS  Google Scholar 

  • Guise TA, Yin JJ et al (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98(7):1544–1549

    PubMed  CAS  Google Scholar 

  • Guise TA, Mohammad KS et al (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 12(20 Pt 2):6213s–6216s

    PubMed  CAS  Google Scholar 

  • Guo Y, Tiedemann K et al (2008) Osteoclast precursors acquire sensitivity to breast cancer derived factors early in differentiation. Bone 43(2):386–393

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    PubMed  CAS  Google Scholar 

  • Hassan S, Baccarelli A et al (2008) Plasma stromal cell-derived factor-1: host derived marker predictive of distant metastasis in breast cancer. Clin Cancer Res 14(2):446–454

    PubMed  CAS  Google Scholar 

  • Hassan S, Ferrario C et al (2009) The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer. Am J Pathol 175(1):66–73

    PubMed  CAS  Google Scholar 

  • Hassan S, Buchanan M, et al (2010) CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int J Cancer

  • Henderson MA, Danks JA et al (2006) Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res 66(4):2250–2256

    PubMed  CAS  Google Scholar 

  • Hershman DL, McMahon DJ et al (2008) Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 26(29):4739–4745

    PubMed  CAS  Google Scholar 

  • Hershman DL, McMahon DJ et al (2010) Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment. J Clin Endocrinol Metab 95(2):559–566

    PubMed  CAS  Google Scholar 

  • Hess KR, Varadhachary GR et al (2006) Metastatic patterns in adenocarcinoma. Cancer 106(7):1624–1633

    PubMed  Google Scholar 

  • Hiraga T, Williams PJ et al (2004) Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res 10(13):4559–4567

    PubMed  CAS  Google Scholar 

  • Hiscox S, Barrett-Lee P et al (2010) Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss. Eur J Cancer 46(12):2187–2195

    PubMed  CAS  Google Scholar 

  • Holen I, Cross SS et al (2005) Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo—a role in tumour cell survival? Breast Cancer Res Treat 92(3):207–215

    PubMed  CAS  Google Scholar 

  • Horne WC, Sanjay A et al (2005) The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev 208:106–125

    PubMed  CAS  Google Scholar 

  • Hotte SJ, Hirte HW et al (2008) 405 POSTER Final results of a Phase I/II study of CTCE-9908, a novel anticancer agent that inhibits CXCR4, in patients with advanced solid cancers. Eur J Cancer Suppl 6(12):127–127

    Google Scholar 

  • Huang EH, Singh B et al (2009) A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res 155(2):231–236

    PubMed  CAS  Google Scholar 

  • Hugo H, Ackland ML et al (2007) Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 213(2):374–383

    PubMed  CAS  Google Scholar 

  • Hussein O, Tiedemann K, et al (2010) Breast cancer cells inhibit spontaneous and bisphosphonate-induced osteoclast apoptosis. Bone 48:202–211

    Google Scholar 

  • Id Boufker H, Lagneaux L et al (2010) The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts. BMC Cancer 10:298

    PubMed  Google Scholar 

  • Iotsova V, Caamano J et al (1997) Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 3(11):1285–1289

    PubMed  CAS  Google Scholar 

  • Jones DH, Nakashima T et al (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440(7084):692–696

    PubMed  CAS  Google Scholar 

  • Josse RG, Hanley DA et al (2007) Diagnosis and treatment of Paget’s disease of bone. Clin Invest Med 30(5):E210–E223

    PubMed  CAS  Google Scholar 

  • Kakonen SM, Mundy GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97(3 Suppl):834–839

    PubMed  Google Scholar 

  • Kang Y, Siegel PM et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    PubMed  CAS  Google Scholar 

  • Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8(4):290–301

    PubMed  CAS  Google Scholar 

  • Kinder M, Chislock E et al (2008a) Metastatic breast cancer induces an osteoblast inflammatory response. Exp Cell Res 314(1):173–183

    PubMed  CAS  Google Scholar 

  • Kinder M, Chislock E et al (2008b) Metastatic breast cancer induces an osteoblast inflammatory response. Exp Cell Res 314(1):173–183

    PubMed  CAS  Google Scholar 

  • Kitazawa S, Kitazawa R (2002) RANK ligand is a prerequisite for cancer-associated osteolytic lesions. J Pathol 198(2):228–236

    PubMed  CAS  Google Scholar 

  • Klein A, Olendrowitz C et al (2009) Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett 276(2):212–220

    PubMed  CAS  Google Scholar 

  • Knowles HJ, Athanasou NA (2009) Canonical and non-canonical pathways of osteoclast formation. Histol Histopathol 24(3):337–346

    PubMed  CAS  Google Scholar 

  • Kodama H, Nose M et al (1991) Essential role of macrophage colony-stimulating factor in the osteoclast differentiation supported by stromal cells. J Exp Med 173(5):1291–1294

    PubMed  CAS  Google Scholar 

  • Koga T, Inui M et al (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428(6984):758–763

    PubMed  CAS  Google Scholar 

  • Kohno N, Aogi K et al (2005) Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23(15):3314–3321

    PubMed  CAS  Google Scholar 

  • Kollet O, Dar A et al (2006) Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12(6):657–664

    PubMed  CAS  Google Scholar 

  • Kollet O, Dar A et al (2007) The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 25:51–69

    PubMed  CAS  Google Scholar 

  • Kondo M, Sakuta K et al (2008) Zoledronate facilitates large-scale ex vivo expansion of functional gammadelta T cells from cancer patients for use in adoptive immunotherapy. Cytotherapy 10(8):842–856

    PubMed  CAS  Google Scholar 

  • Kong YY, Yoshida H et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397(6717):315–323

    PubMed  CAS  Google Scholar 

  • Korah R, Choi L et al (2004) Expression of FGF-2 alters focal adhesion dynamics in migration-restricted MDA-MB-231 breast cancer cells. Breast Cancer Res Treat 88(1):17–28

    PubMed  CAS  Google Scholar 

  • Kozlow W, Guise TA (2005) Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J Mammary Gland Biol Neoplasia 10(2):169–180

    PubMed  Google Scholar 

  • Kyrgidis A, Vahtsevanos K et al (2008) Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 26(28):4634–4638

    PubMed  Google Scholar 

  • Lakkakorpi PT, Vaananen HK (1996) Cytoskeletal changes in osteoclasts during the resorption cycle. Microsc Res Tech 33(2):171–181

    PubMed  CAS  Google Scholar 

  • Le Gall C, Bellahcene A et al (2007) A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res 67(20):9894–9902

    PubMed  Google Scholar 

  • Lee YT (1983) Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 23(3):175–180

    PubMed  CAS  Google Scholar 

  • Lee YC, Huang CF et al (2010) Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29(22):3196–3207

    PubMed  CAS  Google Scholar 

  • Leone BA, Romero A et al (1988) Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis. The GOCS (Grupo Oncologico Cooperativo del Sur) experience. Am J Clin Oncol 11(6):618–622

    PubMed  CAS  Google Scholar 

  • Levine JP (2006) Pharmacologic and nonpharmacologic management of osteoporosis. Clin Cornerstone 8(1):40–53

    PubMed  Google Scholar 

  • Li Z, Schem C et al (2008) Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis. Clin Exp Metastasis 25(4):389–400

    PubMed  Google Scholar 

  • Lipton A (2006) Future treatment of bone metastases. Clin Cancer Res 12(20 Pt 2):6305s–6308s

    PubMed  CAS  Google Scholar 

  • Lipton A, Cook RJ et al (2007a) Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity. Oncologist 12(9):1035–1043

    PubMed  CAS  Google Scholar 

  • Lipton A, Steger GG et al (2007b) Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 25(28):4431–4437

    PubMed  CAS  Google Scholar 

  • Lipton A, Steger GG et al (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14(20):6690–6696

    PubMed  CAS  Google Scholar 

  • Mancino AT, Klimberg VS et al (2001) Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res 100(1):18–24

    PubMed  CAS  Google Scholar 

  • Matsuo K, Irie N (2008) Osteoclast-osteoblast communication. Arch Biochem Biophys 473(2):201–209

    PubMed  CAS  Google Scholar 

  • McHugh KP, Hodivala-Dilke K et al (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105(4):433–440

    PubMed  CAS  Google Scholar 

  • McMahon B, Kwaan HC (2008) The plasminogen activator system and cancer. Pathophysiol Haemost Thromb 36(3–4):184–194

    PubMed  Google Scholar 

  • Mendez-Ferrer S, Michurina TV et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834

    PubMed  CAS  Google Scholar 

  • Meraviglia S, Eberl M et al (2010) In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin Exp Immunol 161(2):290–297

    PubMed  CAS  Google Scholar 

  • Minn AJ, Kang Y et al (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115(1):44–55

    PubMed  CAS  Google Scholar 

  • Mishima S, Nagai A et al (2010) Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. Eur J Haematol 84(6):538–546

    PubMed  CAS  Google Scholar 

  • Miyazaki T, Tanaka S et al (2006) The role of c-Src kinase in the regulation of osteoclast function. Mod Rheumatol 16(2):68–74

    PubMed  CAS  Google Scholar 

  • Mocsai A, Humphrey MB et al (2004) The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA 101(16):6158–6163

    PubMed  CAS  Google Scholar 

  • Morgan H, Tumber A et al (2004) Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J Cancer 109(5):653–660

    PubMed  CAS  Google Scholar 

  • Mori K, Ando K et al (2009) Receptor activator of nuclear factor-kappa B ligand (RANKL) stimulates bone-associated tumors through functional RANK expressed on bone-associated cancer cells? Histol Histopathol 24(2):235–242

    PubMed  CAS  Google Scholar 

  • Mourskaia AA, Northey JJ et al (2007) Targeting aberrant TGF-beta signaling in pre-clinical models of cancer. Anticancer Agents Med Chem 7(5):504–514

    PubMed  CAS  Google Scholar 

  • Mourskaia AA, Dong Z et al (2009) Transforming growth factor-beta1 is the predominant isoform required for breast cancer cell outgrowth in bone. Oncogene 28(7):1005–1015

    PubMed  CAS  Google Scholar 

  • Mulari M, Vaaraniemi J et al (2003) Intracellular membrane trafficking in bone resorbing osteoclasts. Microsc Res Tech 61(6):496–503

    PubMed  CAS  Google Scholar 

  • Muller A, Homey B et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56

    PubMed  CAS  Google Scholar 

  • Mundy GR (1997) Mechanisms of bone metastasis. Cancer 80(8 Suppl):1546–1556

    PubMed  CAS  Google Scholar 

  • Naito A, Azuma S et al (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4(6):353–362

    PubMed  CAS  Google Scholar 

  • Najmi S, Korah R et al (2005) Flavopiridol blocks integrin-mediated survival in dormant breast cancer cells. Clin Cancer Res 11(5):2038–2046

    PubMed  CAS  Google Scholar 

  • Nakamura I, Rodan GA et al (2003) Regulatory mechanism of osteoclast activation. J Electron Microsc (Tokyo) 52(6):527–533

    CAS  Google Scholar 

  • Nakamura I, Duong le T et al (2007) Involvement of alpha(v)beta3 integrins in osteoclast function. J Bone Miner Metab 25(6):337–344

    PubMed  CAS  Google Scholar 

  • Naumovski L, Junutula JR (2010) Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. Curr Opin Mol Ther 12(2):248–257

    PubMed  CAS  Google Scholar 

  • Nautiyal J, Majumder P et al (2009) Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Cancer Lett 283(2):143–151

    PubMed  CAS  Google Scholar 

  • Negishi-Koga T, Takayanagi H (2009) Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 231(1):241–256

    PubMed  CAS  Google Scholar 

  • Neville-Webbe HL, Cross NA et al (2004) Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. Breast Cancer Res Treat 86(3):269–279

    PubMed  CAS  Google Scholar 

  • Onishi T, Hayashi N, et al (2010) Future directions of bone-targeted therapy for metastatic breast cancer. Nat Rev Clin Oncol

  • Ory S, Brazier H et al (2008) Rho GTPases in osteoclasts: orchestrators of podosome arrangement. Eur J Cell Biol 87(8–9):469–477

    PubMed  CAS  Google Scholar 

  • Ottewell PD, Monkkonen H et al (2008) Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst 100(16):1167–1178

    PubMed  CAS  Google Scholar 

  • Park BK, Zhang H et al (2007) NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13(1):62–69

    PubMed  CAS  Google Scholar 

  • Pavlaki M, Zucker S (2003) Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev 22(2–3):177–203

    PubMed  CAS  Google Scholar 

  • Perou CM, Sorlie T et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    PubMed  CAS  Google Scholar 

  • Phadke PA, Mercer RR et al (2006) Kinetics of metastatic breast cancer cell trafficking in bone. Clin Cancer Res 12(5):1431–1440

    PubMed  Google Scholar 

  • Pichot CS, Hartig SM et al (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101(1):38–47

    PubMed  CAS  Google Scholar 

  • Powell GJ, Southby J et al (1991) Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 51(11):3059–3061

    PubMed  CAS  Google Scholar 

  • Rachner TD, Benad P et al (2009) Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis. J Cell Biochem 108(1):106–116

    PubMed  CAS  Google Scholar 

  • Rack B, Juckstock J et al (2010) Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 30(5):1807–1813

    PubMed  CAS  Google Scholar 

  • Reddi AH, Roodman D et al (2003) Mechanisms of tumor metastasis to the bone: challenges and opportunities. J Bone Miner Res 18(2):190–194

    PubMed  CAS  Google Scholar 

  • Richert MM, Vaidya KS et al (2009) Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone. Oncol Rep 21(3):761–767

    PubMed  CAS  Google Scholar 

  • Rose AA, Pepin F et al (2007) Osteoactivin promotes breast cancer metastasis to bone. Mol Cancer Res 5(10):1001–1014

    PubMed  CAS  Google Scholar 

  • Rose AA, Siegel PM (2010) Emerging therapeutic targets in breast cancer bone metastasis. Future Oncol 6(1):55–74

    PubMed  CAS  Google Scholar 

  • Rose AA, Grosset AA et al (2010) Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res 16(7):2147–2156

    PubMed  CAS  Google Scholar 

  • Rosen LS, Gordon D et al (2003) Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98(8):1735–1744

    PubMed  CAS  Google Scholar 

  • Rosen LS, Gordon DH et al (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100(1):36–43

    PubMed  CAS  Google Scholar 

  • Russell RG (2007) Bisphosphonates: mode of action and pharmacology. Pediatrics 119(Suppl 2):S150–S162

    PubMed  Google Scholar 

  • Saad F, Lipton A (2010) SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev 36(2):177–184

    PubMed  CAS  Google Scholar 

  • Saltel F, Chabadel A et al (2008) Actin cytoskeletal organisation in osteoclasts: a model to decipher transmigration and matrix degradation. Eur J Cell Biol 87(8–9):459–468

    PubMed  CAS  Google Scholar 

  • Santini D, Vincenzi B et al (2007) Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 13(15 Pt 1):4482–4486

    PubMed  CAS  Google Scholar 

  • Santini D, Perrone G, et al (2010) Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol

  • Schneider A, Kalikin LM et al (2005) Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology 146(4):1727–1736

    PubMed  CAS  Google Scholar 

  • Schubert A, Schulz H et al (2008) 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 24(6):331–338

    PubMed  CAS  Google Scholar 

  • Sherry MM, Greco FA et al (1986a) Breast cancer with skeletal metastases at initial diagnosis. Distinctive clinical characteristics and favorable prognosis. Cancer 58(1):178–182

    PubMed  CAS  Google Scholar 

  • Sherry MM, Greco FA et al (1986b) Metastatic breast cancer confined to the skeletal system. An indolent disease. Am J Med 81(3):381–386

    PubMed  CAS  Google Scholar 

  • Shimo T, Kubota S et al (2006) Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J Bone Miner Res 21(7):1045–1059

    PubMed  CAS  Google Scholar 

  • Siclari VA, Guise TA et al (2006) Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. Cancer Metastasis Rev 25(4):621–633

    PubMed  CAS  Google Scholar 

  • Singh B, Berry JA et al (2006) Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer. J Surg Res 134(1):44–51

    PubMed  CAS  Google Scholar 

  • Slade MJ, Coombes RC (2007) The clinical significance of disseminated tumor cells in breast cancer. Nat Clin Pract Oncol 4(1):30–41

    PubMed  Google Scholar 

  • Smid M, Wang Y et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol 24(15):2261–2267

    PubMed  CAS  Google Scholar 

  • Smid M, Wang Y et al (2008) Subtypes of breast cancer show preferential site of relapse. Cancer Res 68(9):3108–3114

    PubMed  CAS  Google Scholar 

  • Solomayer EF, Diel IJ et al (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59(3):271–278

    PubMed  CAS  Google Scholar 

  • Soriano P, Montgomery C et al (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64(4):693–702

    PubMed  CAS  Google Scholar 

  • Sorlie T, Perou CM et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874

    PubMed  CAS  Google Scholar 

  • Sorlie T, Tibshirani R et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423

    PubMed  CAS  Google Scholar 

  • Takahashi N, Ejiri S et al (2007) Regulation of osteoclast polarization. Odontology 95(1):1–9

    PubMed  CAS  Google Scholar 

  • Tiedemann K, Hussein O et al (2009) Breast cancer-derived factors stimulate osteoclastogenesis through the Ca2+/protein kinase C and transforming growth factor-beta/MAPK signaling pathways. J Biol Chem 284(48):33662–33670

    PubMed  CAS  Google Scholar 

  • Tjensvoll K, Oltedal S et al (2010) Disseminated tumor cells in bone marrow assessed by TWIST1, cytokeratin 19, and mammaglobin A mRNA predict clinical outcome in operable breast cancer patients. Clin Breast Cancer 10(5):378–384

    PubMed  CAS  Google Scholar 

  • Tomaskovic-Crook E, Thompson EW et al (2009) Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res 11(6):213

    PubMed  Google Scholar 

  • Tondravi MM, McKercher SR et al (1997) Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386(6620):81–84

    PubMed  CAS  Google Scholar 

  • Trimboli AJ, Fukino K et al (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68(3):937–945

    PubMed  CAS  Google Scholar 

  • Vaananen HK, Hentunen T et al (1988) Mechanism of osteoclast mediated bone resorption. Ann Chir Gynaecol 77(5–6):193–196

    PubMed  CAS  Google Scholar 

  • Vaananen HK, Laitala-Leinonen T (2008) Osteoclast lineage and function. Arch Biochem Biophys 473(2):132–138

    PubMed  Google Scholar 

  • Vaananen HK, Zhao H et al (2000) The cell biology of osteoclast function. J Cell Sci 113(Pt 3):377–381

    PubMed  CAS  Google Scholar 

  • van ’t Veer LJ, Dai H et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Google Scholar 

  • van de Vijver MJ, He YD et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009

    PubMed  Google Scholar 

  • Van Overstraeten-Schlogel N, Beguin Y et al (2006) Role of stromal-derived factor-1 in the hematopoietic-supporting activity of human mesenchymal stem cells. Eur J Haematol 76(6):488–493

    PubMed  Google Scholar 

  • von Metzler I, Krebbel H et al (2007) Bortezomib inhibits human osteoclastogenesis. Leukemia 21(9):2025–2034

    Google Scholar 

  • Wada T, Nakashima T et al (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12(1):17–25

    PubMed  CAS  Google Scholar 

  • Wang Y, Klijn JG et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679

    PubMed  CAS  Google Scholar 

  • Wang J, Loberg R et al (2006) The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Rev 25(4):573–587

    PubMed  CAS  Google Scholar 

  • Wang ZQ, Ovitt C et al (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360(6406):741–745

    PubMed  CAS  Google Scholar 

  • Weiss L (1992) Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clin Exp Metastasis 10(3):191–199

    PubMed  CAS  Google Scholar 

  • Wiktor-Jedrzejczak W, Bartocci A et al (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87(12):4828–4832

    PubMed  CAS  Google Scholar 

  • Willipinski-Stapelfeldt B, Riethdorf S et al (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11(22):8006–8014

    PubMed  CAS  Google Scholar 

  • Wilson TJ, Nannuru KC et al (2008) Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand. Cancer Res 68(14):5803–5811

    PubMed  CAS  Google Scholar 

  • Wilson TJ, Nannuru KC et al (2009) Cathepsin G recruits osteoclast precursors via proteolytic activation of protease-activated receptor-1. Cancer Res 69(7):3188–3195

    PubMed  CAS  Google Scholar 

  • Yang L, Moses HL (2008) Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? Cancer Res 68(22):9107–9111

    PubMed  CAS  Google Scholar 

  • Yin JJ, Selander K et al (1999) TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103(2):197–206

    PubMed  CAS  Google Scholar 

  • Yokota A, Kimura S et al (2010) Osteoclasts are involved in the maintenance of dormant leukemic cells. Leuk Res 34(6):793–799

    PubMed  CAS  Google Scholar 

  • Zaidi M, Pazianas M et al (1993) Osteoclast function and its control. Exp Physiol 78(6):721–739

    PubMed  CAS  Google Scholar 

  • Zhang XH, Wang Q et al (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16(1):67–78

    PubMed  CAS  Google Scholar 

  • Zuradelli M, Masci G et al (2009) High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid. Oncologist 14(5):548–556

    PubMed  CAS  Google Scholar 

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Acknowledgments

We apologize to the colleagues whose work was not cited in this review for reasons of space and knowledge limitation. We appreciate the elaborate discussion with our colleagues, with Dr. P.M. Siegel, Dr. M. Murshed and Dr. M. Basik from McGill University. O.H. is supported by the Merit Doctoral Research Scholarship from the Government of Quebec, by Lloyd Carr-Harris Fellowship and by McGill University. S.V.K. holds a Canada Research Chair in Osteoclast Biology.

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  1. Osama Hussein

    Present address: Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt

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  1. Faculty of Dentistry, McGill University, Montreal, Quebec, H3A 1A4, Canada

    Osama Hussein & Svetlana V. Komarova

  2. 740 Dr. Penfield Ave, 2201, Montreal, Quebec, Canada, H3A 1A4

    Svetlana V. Komarova

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Hussein, O., Komarova, S.V. Breast cancer at bone metastatic sites: recent discoveries and treatment targets. J. Cell Commun. Signal. 5, 85–99 (2011). https://doi.org/10.1007/s12079-011-0117-3

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