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Bone. 2014 Apr;61:176-85. doi: 10.1016/j.bone.2014.01.015. Epub 2014 Jan 28.

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.

Author information

1
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
2
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
3
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
4
Knoxville Comprehensive Breast Center, Knoxville, TN, USA.
5
Division of Gastroenterology, San Francisco General Hospital, University of California San Francisco Liver Center, San Francisco, CA, USA.
6
Division of Oncology, Pennsylvania State University, Hershey Cancer Institute, Pennsylvania State Hershey Medical Center, Hershey, PA, USA.
7
Department of Orthopaedic Surgery, Center for Orthopaedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: suvalarryj@uams.edu.

Abstract

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

KEYWORDS:

Chemokine; Osteoclast; Osteolysis; Therapy

PMID:
24486955
PMCID:
PMC3967592
DOI:
10.1016/j.bone.2014.01.015
[Indexed for MEDLINE]
Free PMC Article

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