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

Carmen Wong, Daniele Gilkes, Huafeng Zhang, Jasper Chen, Hong Wei, Pallavi Chaturvedi, Stephanie Fraley, Chun-Ming Wong, Ui-Soon Khoo, Irene Ng, Denis Wirtz, Gregg Semenza (2011) Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation Proc Natl Acad Sci U S A (IF: 9.1) 108(39) 16369-74

Abstract

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.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182724
http://www.ncbi.nlm.nih.gov/pubmed/21911388
http://dx.doi.org/10.1073/pnas.1113483108

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