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

2011; National Academy of Sciences; Volume: 108; Issue: 39 Linguagem: Inglês

10.1073/pnas.1113483108

1091-6490

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

Nitric Oxide and Endothelin Effects

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.