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01-09-2009 | Preclinical Study

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

Authors: Namita Kundu, Xinrong Ma, Dawn Holt, Olga Goloubeva, Suzanne Ostrand-Rosenberg, Amy M. Fulton

Published in: Breast Cancer Research and Treatment | Issue 2/2009

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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Title: Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function
Authors: Namita Kundu
Xinrong Ma
Dawn Holt
Olga Goloubeva
Suzanne Ostrand-Rosenberg
Amy M. Fulton
Publication date: 01-09-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-0180-5

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