Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.
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 α-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.
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Carmen Chak-Lui
CC
Wong
Huafeng
H
Zhang
Daniele M
DM
Gilkes
Jasper
J
Chen
Hong
H
Wei
Pallavi
P
Chaturvedi
Maimon E
ME
Hubbi
Gregg L
GL
Semenza
D000167:Acriflavine / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D004077:Digoxin / Q000494:pharmacology; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D008249:Protein-Lysine 6-Oxidase; D023041:Xenograft Model Antitumor Assays
D051793:Hypoxia-Inducible Factor 1; D000167:Acriflavine; D004077:Digoxin; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase