title: 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.
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Jasper
authors.initials: J
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: Stephanie I
authors.initials: SI
authors.lastname: Fraley
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Ui-Soon
authors.initials: US
authors.lastname: Khoo
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000502:physiology*; D009362:Neoplasm Metastasis
chemical_list: D051793:Hypoxia-Inducible Factor 1; D003094:Collagen