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: Carmen Chak-Lui Wong, Daniele M Gilkes, Huafeng Zhang, Jasper Chen, Hong Wei, Pallavi Chaturvedi, Stephanie I Fraley, Chun-Ming Wong, Ui-Soon Khoo, Irene Oi-Lin Ng, Denis Wirtz, Gregg L Semenza
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 39 Pg. 16369-74 (Sep 27 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21911388 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1
• Collagen

Topics

• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Collagen (metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• Hypoxia-Inducible Factor 1 (genetics, physiology)
• Neoplasm Metastasis