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ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

Publication ,  Journal Article
Hedditch, EL; Gao, B; Russell, AJ; Lu, Y; Emmanuel, C; Beesley, J; Johnatty, SE; Chen, X; Harnett, P; George, J; Williams, RT; Flemming, C ...
Published in: J Natl Cancer Inst
July 2014

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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Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

July 2014

Volume

106

Issue

7

Location

United States

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Grading
  • Kaplan-Meier Estimate
  • Humans
 

Citation

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Hedditch, E. L., Gao, B., Russell, A. J., Lu, Y., Emmanuel, C., Beesley, J., … Henderson, M. J. (2014). ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst, 106(7). https://doi.org/10.1093/jnci/dju149
Hedditch, Ellen L., Bo Gao, Amanda J. Russell, Yi Lu, Catherine Emmanuel, Jonathan Beesley, Sharon E. Johnatty, et al. “ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.J Natl Cancer Inst 106, no. 7 (July 2014). https://doi.org/10.1093/jnci/dju149.
Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, et al. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst. 2014 Jul;106(7).
Hedditch, Ellen L., et al. “ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.J Natl Cancer Inst, vol. 106, no. 7, July 2014. Pubmed, doi:10.1093/jnci/dju149.
Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, Johnatty SE, Chen X, Harnett P, George J, Australian Ovarian Cancer Study Group, Williams RT, Flemming C, Lambrechts D, Despierre E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching P, Beckmann MW, Ekici AB, Hein A, Matsuo K, Hosono S, Nakanishi T, Yatabe Y, Pejovic T, Bean Y, Heitz F, Harter P, du Bois A, Schwaab I, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Lundvall L, Engelholm SA, Brown B, Flanagan J, Metcalf MD, Siddiqui N, Sellers T, Fridley B, Cunningham J, Schildkraut J, Iversen E, Weber RP, Berchuck A, Goode E, Bowtell DD, Chenevix-Trench G, deFazio A, Norris MD, MacGregor S, Haber M, Henderson MJ. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst. 2014 Jul;106(7).
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

July 2014

Volume

106

Issue

7

Location

United States

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Grading
  • Kaplan-Meier Estimate
  • Humans