Abstract 5119: Multiple drug resistance-associated protein 4 (MRP4) may contribute to breast cancer progression by exporting the COX-2 product PGE2.
Authors: Kochel Tyler J. , Reader Jocelyn , Kundu Namita , Li Yanchun , Ma Xinrong , Holt Dawn , Fulton Amy 
Published: August 2014

Cancer is becoming the most prevalent disease in developed countries due to aging populations. Breast cancer is the most frequently diagnosed cancer among women accounting for 23% of total cancer diagnoses and 14% of cancer-related deaths. As with many solid tumors, cyclooxygenase 2 (COX-2) and its enzymatic product, prostaglandin E2 (PGE2), are elevated in breast cancer, and are associated with a poor prognosis. PGE2 initiates various signaling pathways when it binds to each of its four cognate EP receptors. We have previously shown that PGE2 signaling through the EP4 receptor increases the metastatic potential of breast cancer cells. Multiple drug resistance-associated protein 4 (MRP4) is responsible for the active export of PGE2 from the tumor cells, while the prostaglandin transporter (PGT) imports PGE2 for 15-hydroxyprostaglandin dehydrogenase (15-PGDH)-mediated degradation. The role of neither MRP4 nor PGT has been investigated in breast cancer progression. We hypothesize that increased expression of MRP4 would cause increased PGE2 signaling and, therefore, increased metastatic potential in breast cancer. Using a panel of breast cancer cell lines, we demonstrate that highly metastatic tumor cells can express low levels of COX-2, but still achieve high extracellular levels of PGE2. We used MCF10A (immortalized normal breast epithelium), MCF7 (luminal), T47D (luminal), MDA-MB-231 (basal B), 4175 (basal B), MDA-MD-468 (basal A), MDA-MB-436 (Basal B), and SKBR3 (HER2-enriched) cell lines. These cell lines span not only a range of molecular subtypes, but also a range of metastatic potential. MRP4 mRNA and protein expression is increased in tumor cell lines with high metastatic potential while expression of PGT mRNA and protein is decreased in these cells when compared to cells with lower metastatic potential. This inverse relationship between MRP4 and PGT should lead to higher concentrations of extracellular PGE2 in the tumor microenvironment, and this hypothesis is being tested through pharmacologic and genetic approaches. Pharmacologic inhibition of MRP4 with MK571 in vitro results in decreased export of two substrates of MRP4, PGE2 and cyclic-AMP (cAMP). Likewise, genetic suppression by MRP4 shRNA shows that decreased MRP4 expression also results in reduced PGE2 export. This data supports the hypothesis that MRP4 is a critcal step in the PGE2 signaling pathway that leads to high extracellular PGE2, and implicates MRP4 as a possible therapeutic target.

Citation Format: Tyler J. Kochel, Jocelyn Reader, Namita Kundu, Yanchun Li, Xinrong Ma, Dawn Holt, Amy Fulton. Multiple drug resistance-associated protein 4 (MRP4) may contribute to breast cancer progression by exporting the COX-2 product PGE2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5119. doi:10.1158/1538-7445.AM2013-5119