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

  • Wende Kozlow
  • Theresa A. GuiseEmail author
Article

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.

Keywords

bone metastasis osteolytic metastasis parathyroid hormone-related protein skeletal-related event 

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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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of MedicineUniversity of VirginiaCharlottesville
  2. 2.Division of Endocrinology, Department of MedicineUniversity of VirginiaCharlottesville

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