Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 106, Issue 7, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/dju149
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Funding
- Cancer Australia
- Cancer Institute New South Wales
- National Health and Medical Research Council (NHMRC) of Australia
- Ovarian Cancer Research Fund
- US Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- NHMRC
- Cancer Council Victoria
- Cancer Council Queensland
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- NHMRC [496675, 310670, 628903]
- Cancer Institute NSW
- NHMRC career development award
- ELAN Funds of the University of Erlangen-Nuremberg
- Nationaal Kankerplan
- Ministry of Health, Labour and Welfare
- American Cancer Society Early Detection Professorship [120950-SIOP-06-258-06-COUN]
- Entertainment Industry Foundation
- National Cancer Institute, Bethesda, MD [RO1 CA 61107]
- Danish Cancer Society, Copenhagen, Denmark [94 222 52]
- Mermaid I project
- Cancer Research UK [C536/A6689]
- Sherie Hildreth Ovarian Cancer Research Fund
- OHSU Foundation
- [R01 CA122443]
- [P50 CA136393]
- Cancer Research UK [13086] Funding Source: researchfish
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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.
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