title: 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.
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.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Kochel
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.; Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Goloubeva
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.; Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fulton
keywords: 15-PGDH; COX-2; MRP4; PGE2; PGT; TNBC