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.
Recommended Citation
Jung M,
Gao J,
Cheung L,
Bongers A,
Somers K,
Clifton M,
Ramsay E,
Russell A,
Valli E,
Gifford A,
George J,
Kennedy C,
Wakefield M,
Topp M,
Ho G,
Scott C,
Bowtell D,
deFazio A,
Norris M,
Haber M,
Henderson M.
ABCC4/MRP4 contributes to the aggressiveness of Myc-associated epithelial ovarian cancer. Int J Cancer 2020 Oct 15; 147(8):2225-2238