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


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.

SUBMITTER: Wong CC 

PROVIDER: S-EPMC3182724 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Wong Carmen Chak-Lui CC   Gilkes Daniele M DM   Zhang Huafeng H   Chen Jasper J   Wei Hong H   Chaturvedi Pallavi P   Fraley Stephanie I SI   Wong Chun-Ming CM   Khoo Ui-Soon US   Ng Irene Oi-Lin IO   Wirtz Denis D   Semenza Gregg L GL  

Proceedings of the National Academy of Sciences of the United States of America 20110912 39


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 w  ...[more]

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