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Breast Cancer: Basic and Clinical Research

Upregulation of Cyclooxygenase-2/Prostaglandin E2 (COX-2/PGE2) Pathway Member Multiple Drug Resistance-Associated Protein 4 (MRP4) and Downregulation of Prostaglandin Transporter (PGT) and 15-Prostaglandin Dehydrogenase (15-PGDH) in Triple-Negative Breast Cancer

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Breast Cancer: Basic and Clinical Research 2016:10 61-70

Original Research

Published on 25 May 2016

DOI: 10.4137/BCBCR.S38529


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Abstract

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE₂) are indicators of a poor prognosis in breast cancer. Using several independent publicly available breast cancer gene expression databases, we investigated other members of the PGE₂ pathway. PGE₂ is produced by COX-2 and actively exported by multiple drug resistance-associated protein 4 (MRP4) into the extracellular microenvironment, where PGE₂ can bind four cognate EP receptors (EP1–EP4) and initiate diverse biological signaling pathways. Alternatively, PGE₂ is imported via the prostaglandin transporter (PGT) and metabolized by 15-prostaglandin dehydrogenase (15-PGDH/HPGD). We made the novel observation that MRP4, PGT, and 15-PGDH are differentially expressed among distinct breast cancer molecular subtypes; this finding was confirmed in independent datasets. In triple-negative breast cancer, the observed gene expression pattern (high COX-2, high MRP4, low PGT, and low 15-PGDH) would favor high levels of tumor-promoting PGE₂ in the tumor microenvironment that may contribute to the overall poor prognosis of triple-negative breast cancer.



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