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	Tyler J Kochel, Jocelyn C Reader, Xinrong Ma, Namita Kundu, Amy M Fulton
Journal	Oncotarget (Oncotarget) Vol. 8 Issue 4 Pg. 6540-6554 (Jan 24 2017) ISSN: 1949-2553 [Electronic] United States
PMID	28029661 (Publication Type: Journal Article)
Chemical References	ABCC4 protein, human Antineoplastic Agents Multidrug Resistance-Associated Proteins Organic Anion Transporters PTGER4 protein, human Propionates Quinazolines Quinolines Receptors, Prostaglandin E, EP4 Subtype SLCO2A1 protein, human Tyrphostins RTKI cpd verlukast Hydroxyprostaglandin Dehydrogenases 15-hydroxyprostaglandin dehydrogenase Cyclooxygenase 1 Cyclooxygenase 2 PTGS1 protein, human PTGS2 protein, human Dinoprostone
Topics	Animals Antineoplastic Agents (pharmacology) Biological Transport Cell Movement (drug effects) Cyclooxygenase 1 (genetics, metabolism) Cyclooxygenase 2 (genetics, metabolism) Dinoprostone (metabolism) Dose-Response Relationship, Drug Female Gene Expression Regulation, Neoplastic Humans Hydroxyprostaglandin Dehydrogenases (metabolism) MCF-7 Cells Mice, Inbred BALB C Mice, SCID Multidrug Resistance-Associated Proteins (antagonists & inhibitors, genetics, metabolism) Neoplasm Metastasis Organic Anion Transporters (genetics, metabolism) Propionates (pharmacology) Quinazolines (pharmacology) Quinolines (pharmacology) RNA Interference Receptors, Prostaglandin E, EP4 Subtype (genetics, metabolism) Signal Transduction Time Factors Transfection Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism, pathology) Tumor Microenvironment Tyrphostins (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!