title: Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence.
abstract: Metastasis accounts for most of the deaths from breast cancer and the preference of invasive breast cancer metastasising to bone has been widely reported. However, the biological basis of breast cancer osteotropism is not fully understood. This paper provides, for the first time, an integrative, systematic review of evidence of molecular factors that have functional roles in the homing of metastatic breast cancer to the bone. Pubmed, Web of Science and EBSCOhost were searched using keywords and synonyms for molecular, metastasis, breast cancer and bone to identify articles published between January 2004 and August 2016. 4491 potentially relevant citations were retrieved. 63 articles met the inclusion criteria, which were primary studies reporting evidence of molecular factors that have functional roles in predisposing breast cancer bone metastasis in vivo. 12 of those 63 articles that additionally met quality criteria were included in the review. Extracted data were tabulated and key findings that indicated biological mechanisms involved in breast cancer metastasis to bone were synthesised. 15 proteins expressed by breast cancer cells were identified as factors that mediate breast cancer bone metastasis: ICAM-1, cadherin-11, osteoactivin, bone sialoprotein, CCN3, IL-11, CCL2, CITED2, CXCR4, CTGF, OPN, CX3CR1, TWIST1, adrenomedullin and Enpp1. Upregulation or overexpression of one or more of them by breast cancer cells resulted in increased breast cancer metastasis to bone in vivo, except for CCL2 where bone-metastatic cells showed a reduced expression of this factor. All factors identified, here expressed by breast cancer cells, are proteins that are normally expressed in the bone microenvironment and linked to physiologic bone functions. All have a functional role in one of more of the following: cell proliferation and differentiation, bone mineralization and remodelling, cell adhesion and/or chemokine signalling. Six of them (cadherin-11, ICAM-1, OPN, CX3CR1, CCN3 and osteoactivin) have a reported function in cell adhesion and another eight (CCN3, osteoactivin, Enpp1, IL-11, CTGF, TWIST1, adrenomedullin and CITED2) are reported to be involved in cell proliferation and differentiation. This review collates and synthesises published evidence to increase our understanding of the biology of breast cancer osteomimicry in the development of bone metastasis. Findings of this review suggest that changes in expression of proteins in breast cancer cells that confer osteomimicry facilitate homing to bone to enable the development of bone metastasis.
authors.affiliation: Department of Applied Health and Professional Development, Oxford Brookes University, Gipsy Lane, Headington, Oxford, OX3 0BP, UK.
authors.forename: Olugbenga
authors.initials: O
authors.lastname: Awolaran
authors.affiliation: Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford, OX3 0BP, UK. Electronic address: sbrooks@brookes.ac.uk.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: Department of Applied Health and Professional Development, Oxford Brookes University, Gipsy Lane, Headington, Oxford, OX3 0BP, UK.
authors.forename: Verna
authors.initials: V
authors.lastname: Lavender
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D006801:Humans; D058574:Integrin-Binding Sialoprotein / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017370:Interleukin-11 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009362:Neoplasm Metastasis; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; C486381:CITED2 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C527276:CXCR4 protein, human; D015820:Cadherins; D018932:Chemokine CCL2; C503042:GPNMB protein, human; D058574:Integrin-Binding Sialoprotein; D017370:Interleukin-11; D008562:Membrane Glycoproteins; D055514:Nephroblastoma Overexpressed Protein; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D012097:Repressor Proteins; D015534:Trans-Activators; D051879:Twist-Related Protein 1; D053495:Osteopontin; D018799:Intercellular Adhesion Molecule-1; D055513:Connective Tissue Growth Factor; D053607:Adrenomedullin; C086960:osteoblast cadherin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases
keywords: Bone; Breast cancer; Metastasis; Osteomimicry