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Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain

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Abstract

Breast cancer is the most common malignancy and second leading cause of cancer death in women. Ninety percent of mortality in breast cancer is often associated with metastatic progression or relapse in patients. Critical stages in the development of aggressive breast cancer include the growth of primary tumors and their ability to spread to foreign organs and form metastases, as well as the establishment of an independent blood supply within the new tumors. Hence, it is imperative to characterize the key molecules that regulate the metastasis of human breast cancer cells. The expression of CXCR4/CXCL12 in breast tumors has been correlated with a poor prognosis, increased metastasis, resistance to conventional therapeutic agents and a poor outcome in the pathogenesis of breast cancer. However, effective anti-CXCR4 therapy remains a challenge. Here, we will review the putative involvement of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Characterization of signaling events important for breast cancer cell growth and their metastasis to the brain should provide insights into breast cancer therapies and improved, successful treatments for breast cancer.

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Abbreviations

Akt:

Protein kinase B

BBB:

Blood brain barrier

Ca2+ :

Calcium ion

CHK:

Csk homologous kinase

CNS:

Central nervous system

Cox2:

Cyclooxygenase-2 (PTGS2)

CXCL12:

Chemokine (C-X-C motif) ligand 12

CXCR4:

CXC chemokine receptor 4

EAE:

Experimental autoimmune encephalomyelitis

EGFR:

Epidermal growth factor receptor

ErbB2:

Epidermal growth factor receptor 2

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

FAK:

Focal adhesion kinase

FKHRL1:

Forkhead transcription factor like 1

HBMEC:

Human brain microvascular endothelial cells

HER2/Neu:

Epidermal growth factor receptor 2

IL:

Interleukins

KDR/Flt-1:

Kinase insert domain receptor

MAPK:

Mitogen-activated protein (MAP) kinases

MMP:

Matrix metalloproteinases

NF-κB:

Nuclear factor-kappa B

NGF:

Nerve growth factor

NP-1:

Neuropilin-1

PI-3K:

Phosphoinositide 3-kinase

PLC:

Phosphoinositide phospholipase C

RNAi:

RNA interference

SDF-1:

Stromal cell-derived factor-1

TGF-β:

Transforming growth factor beta

VEGF:

Vascular endothelial growth factor

VEGFR1:

Vascular endothelial growth factor receptor 1

YY1B:

Yin Yang 1b transcription factor

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Acknowledgements

Limitations of space preclude extensive citation of the literature; we apologize to those whose work is not mentioned herein. Research in this lab is supported, in part, by National Institutes of Health Grants HL80699 (SA), CA096805 (HA), HL00791708 (CVH), Army Breast Cancer Concept Award (SA), the Susan G. Komen Fellowship (SA).

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  1. Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, 3rd Floor, Boston, MA, 02115, USA

    Cimona V. Hinton, Shalom Avraham & Hava Karsenty Avraham

  2. Harvard Medical School, Boston, MA, USA

    Cimona V. Hinton, Shalom Avraham & Hava Karsenty Avraham

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  1. Cimona V. Hinton
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  2. Shalom Avraham
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  3. Hava Karsenty Avraham
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Correspondence to Hava Karsenty Avraham.

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Hinton, C.V., Avraham, S. & Avraham, H.K. Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 27, 97–105 (2010). https://doi.org/10.1007/s10585-008-9210-2

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  • DOI: https://doi.org/10.1007/s10585-008-9210-2

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