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Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function

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Abstract

Cyclooxygenase-2 (COX-2) is associated with aggressive breast cancers. The COX-2 product prostaglandin E2 (PGE2) acts through four G-protein-coupled receptors designated EP1–4. Malignant and immortalized normal mammary epithelial cell lines express all four EP. The EP4 antagonist AH23848 reduced the ability of tumor cells to colonize the lungs or to spontaneously metastasize from the mammary gland. EP4 gene silencing by shRNA also reduced the ability of mammary tumor cells to metastasize. Metastasis inhibition was lost in mice lacking either functional Natural Killer (NK) cells or interferon-γ. EP4 antagonism inhibited MHC class I expression resulting in enhanced ability of NK cells to lyse mammary tumor target cells. These studies support the hypothesis that EP4 receptor antagonists reduce metastatic potential by facilitating NK-mediated tumor cell killing and that therapeutic targeting of EP4 may be an alternative approach to the use of COX inhibitors to limit metastatic disease.

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Acknowledgments

This work was supported by the United States Department of Defense and the Department of Health and Human Services. We thank the Biostatistics and Flow Cytometry Core Facilities of the University of Maryland Greenebaum Cancer Center.

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Authors and Affiliations

  1. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Namita Kundu, Xinrong Ma, Dawn Holt & Amy M. Fulton

  2. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA

    Olga Goloubeva & Amy M. Fulton

  3. Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, 21250, USA

    Suzanne Ostrand-Rosenberg

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  1. Namita Kundu
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  2. Xinrong Ma
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  3. Dawn Holt
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  4. Olga Goloubeva
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  6. Amy M. Fulton
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Correspondence to Amy M. Fulton.

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Kundu, N., Ma, X., Holt, D. et al. Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat 117, 235–242 (2009). https://doi.org/10.1007/s10549-008-0180-5

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