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

Primary tumors facilitate metastasis by directing bone marrowderived 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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 108; no. 39; pp. 16369 - 16374
Main Authors Wong, Carmen Chak-Lui, Gilkes, Daniele M., Zhang, Huafeng, Chen, Jasper, Wei, Hong, Chaturvedi, Pallavi, Fraley, Stephanie I., Wong, Chun-Ming, Khoo, Ui-Soon, Ng, Irene Oi-Lin, Wirtz, Denis, Semenza, Gregg L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 27.09.2011
National Acad Sciences
Subjects
Biological Sciences
Bone marrow
Bone marrow cells
Breast cancer
breast neoplasms
Breast Neoplasms - pathology
Cancer
Cell Line, Tumor
Cell lines
Collagen
Collagen - metabolism
Collagens
crosslinking
Family members
Female
Gene Knockdown Techniques
Humans
Hypoxia
Hypoxia-Inducible Factor 1 - genetics
Hypoxia-Inducible Factor 1 - physiology
Lungs
Metastasis
mice
Neoplasm Metastasis
Rodents
Tumors
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Summary:Primary tumors facilitate metastasis by directing bone marrowderived 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.
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Contributed by Gregg L. Semenza, August 17, 2011 (sent for review July 25, 2011)
Author contributions: C.C.-L.W., D.M.G., and G.L.S. designed research; C.C.-L.W., D.M.G., H.Z., J.C., H.W., P.C., S.I.F., C.-M.W., U.-S.K., and I.O.-L.N. performed research; D.W. contributed new reagents/analytic tools; C.C.-L.W., D.M.G., and G.L.S. analyzed data; and C.C.-L.W. and G.L.S. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1113483108