期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 90, 期 7, 页码 803-815出版社
SPRINGER
DOI: 10.1007/s00109-011-0855-y
关键词
HIF-1; Targeted therapy; Extracellular matrix; Triple-negative breast cancer; Cardiac glycosides; Individualized therapy
资金
- Emerald Foundation
- National Cancer Institute [U54-CA143868]
- Johns Hopkins Institute for Cell Engineering
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-1 alpha-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.
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