Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 31, Pages E3234-E3242Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1410041111
Keywords
orthotopic transplantation; triple negative breast cancer; oxygen; tumor microenvironment; mammary fat pad implantation
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Funding
- American Cancer Society
- Public Health Service from the National Cancer Institute (NCI) [U54-CA143868]
- National Institute of Biomedical Imaging and Bioengineering [R01-EB016721]
- National Natural Science Foundation of China [81172253]
- Pu Jiang Scholar Program [10PJ1407100]
- Susan G. Komen Foundation
- Japan Science and Technology Agency
- China Scholarship Council
- NCI [K99-CA168746]
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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. Intra-tumoral 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 naive 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.
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