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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 08, 2020
- Source ID
- 10.1002/ijc.33005
Entities
People
- Amanda J. Russell
- Andrew J. Gifford
- Angelika Bongers
- Anna deFazio
- Catherine J Kennedy
- Clare L. Scott
- David D. Bowtell
- Emanuele Valli
- Emma E. Ramsay
- Gwo‐yaw Ho
- Jixuan Gao
- Joshy George
- Klaartje Somers
- Leanna Cheung
- Matthew J. Wakefield
- Michelle Haber
- Michelle J Henderson
- Molly Clifton
- Monique Topp
- MoonSun Jung
- Murray D. Norris
- The Australian Ovarian Cancer Study
Organizations
- Cancer Australia
- Cancer Council New South Wales
- Cancer Council SA
- Cancer Council Tasmania
- Cancer Council Victoria
- Cancer Institute of New South Wales
- National Health and Medical Research Council
- Ovarian Cancer Action
- Ovarian Cancer Australia
- Peter MacCallum Cancer Centre
- Prince of Wales Hospital, Sydney
- United States Army Medical Research and Development Command
- University of New South Wales
- University of Sydney
- WEHI