In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer

Xin Lu, Carol H. Yan, Min Yuan, Yong Wei, Guohong Hu, Yibin Kang

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis, invasion, and metastasis. However, a comparative analysis of the potentially distinct functions of hypoxia in primary tumor growth and organ-specific metastasis has not been reported. Here, we show distinct hypoxia kinetics in tumors generated by the MDA-MB-231 breast cancer sublines with characteristically different primary tumor growth rates and organotropic metastasis potentials. Hypoxia-induced angiogenesis promotes both primary tumor growth and lung metastasis but is nonessential for bone metastasis. Microarray profiling revealed that hypoxia enhances the expression of a significant number of genes in the lung metastasis signature, but only activates a few bone metastasis genes, among which DUSP1 was functionally validated in this study. Despite the different mechanisms by which hypoxia promotes organ-specific metastasis, inhibition of HIF-1α with a dominant-negative form of HIF-1α or 2-methoxyestradiol reduced metastasis to both lung and bone. Consistent with the extensive functional overlap of hypoxia in promoting primary tumor growth and lung metastasis, a 45-gene hypoxia response signature efficiently stratifies breast cancer patients with low or high risks of lung metastasis, but not for bone metastasis. Our study shows distinct functions of hypoxia in regulating angiogenesis and metastasis in different organ microenvironments and establishes HIF-1α as a promising target for controlling organotropic metastasis of breast cancer.

Original languageEnglish (US)
Pages (from-to)3905-3914
Number of pages10
JournalCancer Research
Volume70
Issue number10
DOIs
StatePublished - May 15 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer'. Together they form a unique fingerprint.

Cite this