Journal of Molecular Medicine

, Volume 90, Issue 7, pp 803–815

Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis

  • Carmen Chak-Lui Wong
  • Huafeng Zhang
  • Daniele M. Gilkes
  • Jasper Chen
  • Hong Wei
  • Pallavi Chaturvedi
  • Maimon E. Hubbi
  • Gregg L. Semenza
Original Article

DOI: 10.1007/s00109-011-0855-y

Cite this article as:
Wong, C.CL., Zhang, H., Gilkes, D.M. et al. J Mol Med (2012) 90: 803. doi:10.1007/s00109-011-0855-y

Abstract

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b+ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

Keywords

HIF-1 Targeted therapy Extracellular matrix Triple-negative breast cancer Cardiac glycosides Individualized therapy 

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Carmen Chak-Lui Wong
    • 1
    • 2
    • 5
  • Huafeng Zhang
    • 1
    • 3
    • 6
  • Daniele M. Gilkes
    • 1
    • 2
  • Jasper Chen
    • 1
    • 2
  • Hong Wei
    • 1
    • 2
  • Pallavi Chaturvedi
    • 1
    • 2
  • Maimon E. Hubbi
    • 1
    • 2
  • Gregg L. Semenza
    • 1
    • 2
    • 3
    • 4
  1. 1.Vascular Program, Institute for Cell EngineeringJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.McKusick-Nathans Institute of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Departments of Pediatrics, Medicine, Radiation Oncology, and Biological ChemistryJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of PathologyThe University of Hong KongHong KongHong Kong
  6. 6.School of Life ScienceUniversity of Science and Technology of ChinaHefeiChina

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