ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

Ellen L. Hedditch(Cancer Institute of New South Wales), Bo Gao(Millennium Institute), Amanda J. Russell(Cancer Institute of New South Wales), Yi Lu(QIMR Berghofer Medical Research Institute), Catherine Emmanuel(Millennium Institute), Jonathan Beesley(QIMR Berghofer Medical Research Institute), Sharon E. Johnatty(QIMR Berghofer Medical Research Institute), Xiaoqing Chen(QIMR Berghofer Medical Research Institute), Paul R. Harnett(The University of Sydney), Joshy George(Cancer Institute of New South Wales), Rebekka Williams(Cancer Institute of New South Wales), Claudia L. Flemming(Cancer Institute of New South Wales), Diether Lambrechts(Cancer Institute of New South Wales), Evelyn Despierre(Cancer Institute of New South Wales), Sandrina Lambrechts(Cancer Institute of New South Wales), Ignace Vergote(Cancer Institute of New South Wales), Beth Y. Karlan(Cedars-Sinai Medical Center), Jenny Lester(Cedars-Sinai Medical Center), Sandra Oršulić(Cedars-Sinai Medical Center), Christine Walsh(Cedars-Sinai Medical Center), Peter A. Fasching(University of California, Los Angeles), Matthias W. Beckmann(Friedrich-Alexander-Universität Erlangen-Nürnberg), Arif B. Ekici(Cancer Institute of New South Wales), Alexander Hein(Friedrich-Alexander-Universität Erlangen-Nürnberg), Keitaro Matsuo(Cancer Institute of New South Wales), Satoyo Hosono(Cancer Institute of New South Wales), Toru Nakanishi(Cancer Institute of New South Wales), Yasushi Yatabe(Cancer Institute of New South Wales), Tanja Pejović(Oregon Health & Science University), Yukie T. Bean(Oregon Health & Science University), Florian Heitz(Friedrich-Alexander-Universität Erlangen-Nürnberg), Philipp Harter(Cancer Institute of New South Wales), Andreas du Bois(Cancer Institute of New South Wales), Ira Schwaab(Cancer Institute of New South Wales), Estrid Høgdall(University of Copenhagen), Susanne K. Kjær(Cancer Institute of New South Wales), Allan Jensen(Cancer Institute of New South Wales), Claus Høgdall(Cancer Institute of New South Wales), Lene Lundvall(Cancer Institute of New South Wales), Svend Aage Engelholm(University of Copenhagen), Bob Brown(Cancer Institute of New South Wales), James M. Flanagan(Cancer Institute of New South Wales), Michelle Metcalf(Cancer Institute of New South Wales), Nadeem Siddiqui(Cancer Institute of New South Wales), Thomas A. Sellers(University of South Florida), Brooke L. Fridley(Cancer Institute of New South Wales), Julie M. Cunningham(Mayo Clinic), Joellen Schildkraut(Duke University), Ed Iversen(Duke University), Rachel Palmieri Weber(Cancer Institute of New South Wales), Andrew Berchuck(Duke University), Ellen L. Goode(Cancer Institute of New South Wales), David D.L. Bowtell(Cancer Institute of New South Wales), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Anna DeFazio(Millennium Institute), Murray D. Norris(Cancer Institute of New South Wales), Stuart MacGregor(QIMR Berghofer Medical Research Institute), Michelle Haber(Cancer Institute of New South Wales), Michelle J. Henderson(Cancer Institute of New South Wales)
JNCI Journal of the National Cancer Institute
June 23, 2014
10.1093/jnci/dju149
Cited by 228Open Access
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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.

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