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Contributed by Gregg L. Semenza, August 17, 2018 (sent for review June 6, 2018; reviewed by Jonathan Sleeman and Cormac T. Taylor)
Significance
In order for a single breast cancer cell to form a recurrent tumor after therapy or a metastasis at a distant site such as the lung, it must have the properties of a breast cancer stem cell. In this paper, we show that adenosine receptor 2B (A2BR) plays a critical role in breast cancer stem cell specification. Adenosine receptor 2A (A2AR) signaling has been shown to play an important role in enabling cancer cells to evade antitumor immunity and A2AR-selective inhibitors are in clinical trials. Our results suggest that inhibiting A2BR may also provide therapeutic benefit to breast cancer patients.
Abstract
Breast cancer stem cells (BCSCs), which are characterized by a capacity for unlimited self-renewal and for generation of the bulk cancer cell population, play a critical role in cancer relapse and metastasis. Hypoxia is a common feature of the cancer microenvironment that stimulates the specification and maintenance of BCSCs. In this study, we found that hypoxia increased expression of adenosine receptor 2B (A2BR) in human breast cancer cells through the transcriptional activity of hypoxia-inducible factor 1. The binding of adenosine to A2BR promoted BCSC enrichment by activating protein kinase C-δ, which phosphorylated and activated the transcription factor STAT3, leading to increased expression of interleukin 6 and NANOG, two key mediators of the BCSC phenotype. Genetic or pharmacological inhibition of A2BR expression or activity decreased hypoxia- or adenosine-induced BCSC enrichment in vitro, and dramatically impaired tumor initiation and lung metastasis after implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice. These data provide evidence that targeting A2BR might be an effective strategy to eradicate BCSCs.
Footnotes
- ↵1To whom correspondence should be addressed. Email: gsemenza{at}jhmi.edu.
Author contributions: G.L.S. designed research; J.L., H.L., D.S., and S.S. performed research; Y.L. contributed new reagents/analytic tools; J.L. and G.L.S. analyzed data; and J.L. and G.L.S. wrote the paper.
Reviewers: J.S., University of Heidelberg; and C.T.T., University College Dublin Conway Institute.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1809695115/-/DCSupplemental.
Published under the PNAS license.
Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment
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