Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Ting Wang, Daniele M. Gilkes, Naoharu Takano, Lisha Xiang, Weibo Luo, Corey J. Bishop, Pallavi Chaturvedi, Jordan J. Green, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

339 Scopus citations


Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)E3234-E3242
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
StatePublished - Aug 5 2014


  • Mammary fat pad implantation
  • Orthotopic transplantation
  • Oxygen
  • Triple negative breast cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • General


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