RESUMO
The cyclooxygenase-2 (COX-2) enzyme and major lipid product, prostaglandin E2 (PGE2) are elevated in many solid tumors including those of the breast and are associated with a poor prognosis. Targeting this enzyme is somewhat effective in preventing tumor progression, but is associated with cardiotoxic secondary effects when used chronically. PGE2 functions by signaling through four EP receptors (EP1-4), resulting in several different cellular responses, many of which are pro-tumorigenic, and there is growing interest in the therapeutic potential of targeting EP4 and EP2. Other members in this signaling pathway are gaining more attention. PGE2 is transported out of and into cells by two unique transport proteins. Multiple Drug Resistance-Associated Protein 4 (MRP4) and Prostaglandin Transporter (PGT) modulate PGE2 signaling by increasing or decreasing the levels of PGE2 available to cells. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) metabolizes PGE2 and silences the pathway in this manner. The purpose of this review is to summarize the extensive data supporting the importance of the COX-2 pathway in tumor biology with a focus on more recently described pathway members and their role in modulating PGE2 signaling. This review describes evidence supporting roles for MRP4, PGT and 15-PGDH in several tumor types with an emphasis on the roles of these proteins in breast cancer. Defining the importance of these latter pathway members will be key to developing new therapeutic approaches that exploit the tumor-promoting COX-2 pathway.
Assuntos
Dinoprostona/metabolismo , Hidroxiprostaglandina Desidrogenases/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Dinoprostona/genética , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Transportadores de Ânions Orgânicos/genéticaRESUMO
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.
Assuntos
Movimento Celular , Dinoprostona/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/farmacologia , Transporte Biológico , Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidroxiprostaglandina Desidrogenases/metabolismo , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Metástase Neoplásica , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Propionatos/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Interferência de RNA , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Tirfostinas/farmacologiaRESUMO
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.