Abstract 4132: Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer

Abstract

Abstract Introduction: MRP4 is responsible for the active export of prostaglandin E2 (PGE2) from cells. PGE2, derived from cyclooxygenase-2-mediated synthesis, contributes to tumor growth and metastasis of many epithelial tumors; however, the role of MRP4 in breast cancer has not been investigated. Methods: We employed publicly available breast cancer gene expression datasets and a panel of breast cancer cell lines to examine the expression and function of MRP4 as well as other members of the PGE2 pathway. In contrast to the export function of MRP4, the prostaglandin transporter PGT/SLCO2A1 imports PGE2 into the cell where 15-prostaglandin dehydrogenase (5-PGDH/HPGD) metabolizes PGE2 to terminate ligand-mediated activation of the prostaglandin E (EP) receptors. Results: We found that ABCC4, which encodes the MRP4 protein, is widely expressed in breast cancer but breast cancer subtypes have different expression profiles of PGE2 pathway members. ABCC4/MRP4 is elevated more frequently in basal breast tumors than in apocrine or luminal tumors. This is the first report that elevated expression of MRP4 is found in breast cancer subtypes (basal, HER2-enriched) with the worst prognoses. ABCC4 expression was also higher in breast cancer-associated stroma compared to healthy mammary tissue. Basal-type tumors also expressed the highest levels of PTGS2/COX-2 while the genes responsible for PGE2 metabolism (HPGD and SLCO2A1) are negatively correlated with TNBC. The same pattern was observed in breast cancer cell lines, where basal-type and HER2-enriched cell lines highly express MRP4 but luminal breast cancers do not. HPGD was decreased in most cancer cell lines compared to MCF10A immortalized cells, consistent with the known tumor suppressor role of HPGD/15PGDH. MRP4 exports PGE2 which was reduced in the presence of MRP4 small m.w. inhibitors or by MRP4 gene silencing. Lastly, expression of shMRP4 in highly metastatic, basal-type MDA-MB-231 human breast cancer cells reduced the ability of these cells to spontaneously metastasize to the lungs of NOD/SCID mice but did not affect the tumor growth properties of tumor cells implanted proximal to the mammary gland. Conclusions: Elevated MRP4 is a characteristic of aggressive breast cancer subtypes and is partially responsible for the high levels of PGE2 in the tumor microenvironment. Silencing of MRP4 reduces spontaneous metastasis in a xenograft model of TNBC. Further investigation of MRP4 as a potential therapeutic target is warranted. Citation Format: Tyler Kochel, Xinrong Ma, Namita Kundu, Jocelyn Reader, Olga Goloubeva, Amy M. Fulton. Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4132.