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

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 (US)
Article numberdju149
JournalJournal of the National Cancer Institute
Volume106
Issue number7
DOIs
StatePublished - Jul 9 2014

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Ovarian Neoplasms
ATP-Binding Cassette Transporters
Gene Expression
Survival
Confidence Intervals
Cell Movement
Neoplasms
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Genome-Wide Association Study
Kaplan-Meier Estimate
Microarray Analysis
Drug Resistance
Small Interfering RNA
Genes
Single Nucleotide Polymorphism
Real-Time Polymerase Chain Reaction
Immunohistochemistry
Alleles
Cholesterol
Lipids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. Journal of the National Cancer Institute, 106(7), [dju149]. https://doi.org/10.1093/jnci/dju149

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

In: Journal of the National Cancer Institute, Vol. 106, No. 7, dju149, 09.07.2014.

Research output: Contribution to journalArticle

Hedditch, EL, Gao, B, Russell, AJ, Lu, Y, Emmanuel, C, Beesley, J, Johnatty, SE, Chen, X, Harnett, P, George, J, 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 2014, 'ABCA transporter gene expression and poor outcome in epithelial ovarian cancer', Journal of the National Cancer Institute, vol. 106, no. 7, dju149. https://doi.org/10.1093/jnci/dju149
Hedditch, Ellen L. ; Gao, Bo ; Russell, Amanda J. ; Lu, Yi ; Emmanuel, Catherine ; Beesley, Jonathan ; Johnatty, Sharon E. ; Chen, Xiaoqing ; Harnett, Paul ; George, Joshy ; Williams, Rebekka T. ; Flemming, Claudia ; Lambrechts, Diether ; Despierre, Evelyn ; Lambrechts, Sandrina ; Vergote, Ignace ; Karlan, Beth ; Lester, Jenny ; Orsulic, Sandra ; Walsh, Christine ; Fasching, Peter ; Beckmann, Matthias W. ; Ekici, Arif B. ; Hein, Alexander ; Matsuo, Keitaro ; Hosono, Satoyo ; Nakanishi, Toru ; Yatabe, Yasushi ; Pejovic, Tanja ; Bean, Yukie ; Heitz, Florian ; Harter, Philipp ; Du Bois, Andreas ; Schwaab, Ira ; Hogdall, Estrid ; Kjaer, Susan K. ; Jensen, Allan ; Hogdall, Claus ; Lundvall, Lene ; Engelholm, Svend Aage ; Brown, Bob ; Flanagan, James ; Metcalf, Michelle D. ; Siddiqui, Nadeem ; Sellers, Thomas ; Fridley, Brooke ; Cunningham, Julie ; Schildkraut, Joellen ; Iversen, Ed ; Weber, Rachel P. ; Berchuck, Andrew ; Goode, Ellen ; Bowtell, David D. ; Chenevix-Trench, Georgia ; Defazio, Anna ; Norris, Murray D. ; Macgregor, Stuart ; Haber, Michelle ; Henderson, Michelle J. / ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 7.
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title = "ABCA transporter gene expression and poor outcome in epithelial ovarian cancer",
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.",
author = "Hedditch, {Ellen L.} and Bo Gao and Russell, {Amanda J.} and Yi Lu and Catherine Emmanuel and Jonathan Beesley and Johnatty, {Sharon E.} and Xiaoqing Chen and Paul Harnett and Joshy George and Williams, {Rebekka T.} and Claudia Flemming and Diether Lambrechts and Evelyn Despierre and Sandrina Lambrechts and Ignace Vergote and Beth Karlan and Jenny Lester and Sandra Orsulic and Christine Walsh and Peter Fasching and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Alexander Hein and Keitaro Matsuo and Satoyo Hosono and Toru Nakanishi and Yasushi Yatabe and Tanja Pejovic and Yukie Bean and Florian Heitz and Philipp Harter and {Du Bois}, Andreas and Ira Schwaab and Estrid Hogdall and Kjaer, {Susan K.} and Allan Jensen and Claus Hogdall and Lene Lundvall and Engelholm, {Svend Aage} and Bob Brown and James Flanagan and Metcalf, {Michelle D.} and Nadeem Siddiqui and Thomas Sellers and Brooke Fridley and Julie Cunningham and Joellen Schildkraut and Ed Iversen and Weber, {Rachel P.} and Andrew Berchuck and Ellen Goode and Bowtell, {David D.} and Georgia Chenevix-Trench and Anna Defazio and Norris, {Murray D.} and Stuart Macgregor and Michelle Haber and Henderson, {Michelle J.}",
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month = "7",
day = "9",
doi = "10.1093/jnci/dju149",
language = "English (US)",
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TY - JOUR

T1 - ABCA transporter gene expression and poor outcome in epithelial ovarian cancer

AU - Hedditch, Ellen L.

AU - Gao, Bo

AU - Russell, Amanda J.

AU - Lu, Yi

AU - Emmanuel, Catherine

AU - Beesley, Jonathan

AU - Johnatty, Sharon E.

AU - Chen, Xiaoqing

AU - Harnett, Paul

AU - George, Joshy

AU - Williams, Rebekka T.

AU - Flemming, Claudia

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Karlan, Beth

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Walsh, Christine

AU - Fasching, Peter

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Hein, Alexander

AU - Matsuo, Keitaro

AU - Hosono, Satoyo

AU - Nakanishi, Toru

AU - Yatabe, Yasushi

AU - Pejovic, Tanja

AU - Bean, Yukie

AU - Heitz, Florian

AU - Harter, Philipp

AU - Du Bois, Andreas

AU - Schwaab, Ira

AU - Hogdall, Estrid

AU - Kjaer, Susan K.

AU - Jensen, Allan

AU - Hogdall, Claus

AU - Lundvall, Lene

AU - Engelholm, Svend Aage

AU - Brown, Bob

AU - Flanagan, James

AU - Metcalf, Michelle D.

AU - Siddiqui, Nadeem

AU - Sellers, Thomas

AU - Fridley, Brooke

AU - Cunningham, Julie

AU - Schildkraut, Joellen

AU - Iversen, Ed

AU - Weber, Rachel P.

AU - Berchuck, Andrew

AU - Goode, Ellen

AU - Bowtell, David D.

AU - Chenevix-Trench, Georgia

AU - Defazio, Anna

AU - Norris, Murray D.

AU - Macgregor, Stuart

AU - Haber, Michelle

AU - Henderson, Michelle J.

PY - 2014/7/9

Y1 - 2014/7/9

N2 - 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.

AB - 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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