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Breast Cancer Metastasis to Bone: Mechanisms of Osteolysis and Implications for Therapy

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The most common skeletal complication of breast cancer is osteolytic bone metastasis. Bone metastases are present in 80% of patients with advanced disease and cause significant morbidity. They are most often osteolytic, but can be osteoblastic or mixed. Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases. Tumor cell gene expression is modified by interaction with bone-derived factors. For example, parathyroid hormone related protein (PTHrP), a tumor cell factor, is upregulated by bone-derived transforming growth factor β (TGFβ). Tumor cell factors, in turn, act upon bone cells to cause dysregulated bone destruction and formation. PTHrP increases osteoblast expression of RANK (receptor activator of NFκB) ligand which, in turn, activates osteoclasts. PTHrP-independent osteolytic factors, such as interleukin [IL]-11 and IL-8, also contribute to the vicious cycle. Other tumor-bone interactions, such as stimulation of tumor-homing through the CXCR4 chemokine receptor by its bone-derived ligand stromal-derived factor-1 (SDF-1), may be responsible for the site-specific predilection of breast cancer for bone. These factors and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.

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Abbreviations

AI:

aromatase inhibitor

BMP:

bone morphogenetic protein

CT:

computed tomography

CTGF:

connective tissue growth factor

EGF:

ET-epidermal growth factor

1:

endothelin-1

FGF:

fibroblast growth factor

HHM:

hypercalcemia of malignancy

IGF:

insulin-like growth factor

IL:

interleukin

LPA:

lysophosphatidic acid

MAP:

M-mitogen-activated protein

CSF:

macrophage colony-stimulating factor

MMP:

matrix metalloproteinase

MRI:

magnetic resonance imaging

NFκB:

nuclear factor kappa B

OPG:

osteoprotegerin

PCR:

polymerase chain reaction

PDGF:

platelet-derived growth factor

PET:

positron emission tomography

PTH:

parathyroid hormone

PTHrP:

parathyroid hormone-related protein

RANK:

receptor activator of NFκB

SDF:

stromal-derived factor

SERM:

selective estrogen-receptor modulator

SPECT:

single photon emission computed tomography

SRE:

skeletal-related event

TGF:

transforming growth factor

TNF:

tumor necrosis factor

VEGF:

vascular endothelial growth factor

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Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia

    Wende Kozlow & Theresa A. Guise

  2. Division of Endocrinology, Department of Medicine, University of Virginia, P.O. Box 801419, Charlottesville, VA, 22908

    Theresa A. Guise

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  1. Wende Kozlow
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Kozlow, W., Guise, T.A. Breast Cancer Metastasis to Bone: Mechanisms of Osteolysis and Implications for Therapy. J Mammary Gland Biol Neoplasia 10, 169–180 (2005). https://doi.org/10.1007/s10911-005-5399-8

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