Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer

The cyclooxygenase-2 (COX-2) enzyme and major lipid product, prostaglandin E-2 (PGE(2)) 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. PGE(2) 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. PGE(2) is transported out of and into cells by two unique transport proteins. Multiple Drug Resistance-Associated Protein 4 (MRP4) and Prostaglandin Transporter (PGT) modulate PGE(2) signaling by increasing or decreasing the levels of PGE(2) available to cells. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) metabolizes PGE(2) 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 PGE(2) 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. (C) 2014 Published by Elsevier Inc.