ABCA transporter gene expression and poor outcome in epithelial ovarian cancer

Ellen L. Hedditch, Bo Gao, Amanda J. Russell, Yi Lu, Catherine Emmanuel, Jonathan Beesley, Sharon E. Johnatty, Xiaoqing Chen, Paul Harnett, Joshy George, Rebekka T. Williams, Claudia Flemming, Diether Lambrechts, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Beth Karlan, Jenny Lester, Sandra Orsulic, Christine WalshPeter Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Keitaro Matsuo, Satoyo Hosono, Toru Nakanishi, Yasushi Yatabe, Tanja Pejovic, Yukie Bean, Florian Heitz, Philipp Harter, Andreas Du Bois, Ira Schwaab, Estrid Hogdall, Susan K. Kjaer, Allan Jensen, Claus Hogdall, Lene Lundvall, Svend Aage Engelholm, Bob Brown, James Flanagan, Michelle D. Metcalf, Nadeem Siddiqui, Thomas Sellers, Brooke Fridley, Julie Cunningham, Joellen Schildkraut, Ed Iversen, Rachel P. Weber, Andrew Berchuck, Ellen Goode, David D. Bowtell, Georgia Chenevix-Trench, Anna Defazio, Murray D. Norris, Stuart Macgregor, Michelle Haber, Michelle J. Henderson

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103 Scopus citations

Abstract

Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Results Associations with outcome were observed with ABC transporters of the A subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P =. 001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Conclusions Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Original languageEnglish
Article numberdju149
JournalJournal of the National Cancer Institute
Volume106
Issue number7
DOIs
StatePublished - 9 Jul 2014
Externally publishedYes

Bibliographical note

Funding Information:
This project has been supported by grants from Cancer Australia, Cancer Institute New South Wales, and the National Health and Medical Research Council (NHMRC) of Australia. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith. The AOCS was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729, NHMRC, Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, the Cancer Foundation of Western Australia, and Cancer Council Tasmania. G. Chenevix-Trench is a Senior Principal Research fellow of the NHMRC. Y. Lu is funded by NHMRC grant 496675, B. Gao is supported by postgraduate scholarships from NHMRC and Cancer Institute NSW, and S. MacGregor is supported by an NHMRC career development award. The Gynaecological Oncology Biobank at Westmead is a member of the Australasian Biospecimen Network-Oncology group, funded by the NHMRC (Enabling Grants 310670 and 628903) and Cancer Institute NSW. Ovarian Cancer Association Consortium member sites: The Bavarian study was supported by ELAN Funds of the University of Erlangen-Nuremberg. The Belgian study was funded by Nationaal Kankerplan. The Japanese study was funded by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare. The LAX study (Women’s Cancer Program) was supported by the American Cancer Society Early Detection Professorship (120950-SIOP-06-258-06-COUN) and Entertainment Industry Foundation. Funding for MALOVA was provided by research grant RO1 CA 61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project. The Mayo Clinic study was supported by R01 CA122443, P50 CA136393. SCOTROC biological studies were supported by Cancer Research UK (grant C536/A6689). The Oregon study was funded by Sherie Hildreth Ovarian Cancer Research Fund and the OHSU Foundation. SCOTROC1 was funded by Cancer Research UK.

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