Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation

Carmen Chak Lui Wong, Daniele M. Gilkes, Huafeng Zhang, Jasper Chen, Hong Wei, Pallavi Chaturvedi, Stephanie I. Fraley, Chun Ming Wong, Ui Soon Khoo, Irene Oi Lin Ng, Denis Wirtz, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

264 Scopus citations


Primary tumors facilitate metastasis by directing bone marrow-derived cells (BMDCs) to colonize the lungs before the arrival of cancer cells. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of breast cancer metastatic niche formation through induction of multiple members of the lysyl oxidase (LOX) family, including LOX, LOX-like 2, and LOX-like 4, which catalyze collagen cross-linking in the lungs before BMDC recruitment. Only a subset of LOX family members was expressed in any individual breast cancer, but HIF-1 was required for expression in each case. Knockdown of HIF-1 or hypoxia-induced LOX family members reduced collagen cross-linking, CD11b + BMDC recruitment, and metastasis formation in the lungs of mice after orthotopic transplantation of human breast cancer cells. Metastatic niche formation is an HIF-1-dependent event during breast cancer progression.

Original languageEnglish (US)
Pages (from-to)16369-16374
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 27 2011


  • Extracellular matrix
  • Lung metastasis

ASJC Scopus subject areas

  • General


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