title: Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer.
abstract: Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15-PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer.
authors.affiliation: University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Kochel
authors.affiliation: University of Maryland School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Jocelyn C
authors.initials: JC
authors.lastname: Reader
authors.affiliation: University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Ma
authors.affiliation: University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Kundu
authors.affiliation: University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.|Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fulton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D002465:Cell Movement / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D006911:Hydroxyprostaglandin Dehydrogenases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011422:Propionates; D011799:Quinazolines; D011804:Quinolines; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020032:Tyrphostins; C073492:ABCC4 protein, human; C545650:PTGER4 protein, human; C503526:SLCO2A1 protein, human; C101044:RTKI cpd; C059141:verlukast; C035859:15-hydroxyprostaglandin dehydrogenase; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human
keywords: MRP4; PGE2; TNBC; breast cancer; metastasis