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

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.

journal_name

Int J Cancer

authors

Jung M,Gao J,Cheung L,Bongers A,Somers K,Clifton M,Ramsay EE,Russell AJ,Valli E,Gifford AJ,George J,Kennedy CJ,Wakefield MJ,Topp M,Ho GY,Australian Ovarian Cancer Study.,Scott CL,Bowtell DD,deFazio A,Norris MD,Hab

doi

10.1002/ijc.33005

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

2225-2238

issue

8

eissn

0020-7136

issn

1097-0215

journal_volume

147

pub_type

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