Title

ABCC4/MRP4 contributes to the aggressiveness of Myc-associated epithelial ovarian cancer.

Document Type

Article

Publication Date

10-15-2020

Publication Title

International journal of cancer. Journal international du cancer

Keywords

JGM, Carcinoma, Endometrioid, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cystadenocarcinoma, Serous, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Multidrug Resistance-Associated Proteins, Ovarian Neoplasms, Prognosis, RNA, Small Interfering, Survival Rate

JAX Source

Int J Cancer 2020 Oct 15; 147(8):2225-2238

Volume

147

Issue

8

First Page

2225

Last Page

2238

ISSN

1097-0215

PMID

32277480

DOI

https://doi.org/10.1002/ijc.33005

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.

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