ABCC4/MRP4 contributes to the aggressiveness of Myc‐associated epithelial ovarian cancer. Issue 8 (8th May 2020)

• Record Type: Journal Article
• Authors: Jung, Moonsun; Gao, Jixuan; Cheung, Leanna; Bongers, Angelika; Somers, Klaartje; Clifton, Molly; Ramsay, Emma E.; Russell, Amanda J.; Valli, Emanuele; Gifford, Andrew J.; George, Joshy; Kennedy, Catherine J.; Wakefield, Matthew J.; Topp, Monique; Ho, Gwo‐Yaw; Scott, Clare L.; Bowtell, David D.; deFazio, Anna; Norris, Murray D.; Haber, Michelle; Henderson, Michelle J.
• Is Part Of: International journal of cancer. Volume 147:Issue 8(2020)
• Page Start: 2225
• Page End: 2238
• Publication Date: 2020-05-08
• Subjects: ABCC4/MRP4 -- epithelial ovarian cancer -- Myc‐driven cancers -- novel therapeutic targets; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33005
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP‐binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4 /MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4 /MRP4, previously shown to be directly regulated by c‐Myc/N‐Myc, was associated with poor prognosis in endometrioid EOC ( P = .001) as well as in a subset of serous EOC with a "high‐ MYCN " profile (C5/proliferative; P = .019). Transient siRNA‐mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5‐like serous cells compared to non‐C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient‐derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc‐associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC. Abstract : What's new? Epithelial ovarian cancer (EOC) generally has an extremely poor prognosis, and new therapies are urgently needed. In this study, the authors examined a multidrug‐resistance efflux pump called MRP4, which is regulated by the Myc oncogene. They found that increased expression of MRP4 was associated with poor prognosis, and that siRNA‐mediated knockdown of MRP4 led to decreased growth, migration, and invasion of EOC cells in vitro and tumors in vivo. These results suggest that MRP4 may provide a valuable therapeutic target for certain EOC tumors.