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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.

SUBMITTER: Hedditch EL

PROVIDER: S-EPMC4110473 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Hedditch Ellen L EL Gao Bo B Russell Amanda J AJ Lu Yi Y Emmanuel Catherine C Beesley Jonathan J Johnatty Sharon E SE Chen Xiaoqing X Harnett Paul P George Joshy J Williams Rebekka T RT Flemming Claudia C Lambrechts Diether D Despierre Evelyn E Lambrechts Sandrina S Vergote Ignace I Karlan Beth B Lester Jenny J Orsulic Sandra S Walsh Christine C Fasching Peter P Beckmann Matthias W MW Ekici Arif B AB Hein Alexander A Matsuo Keitaro K Hosono Satoyo S Nakanishi Toru T Yatabe Yasushi Y Pejovic Tanja T Bean Yukie Y Heitz Florian F Harter Philipp P du Bois Andreas A Schwaab Ira I Hogdall Estrid E Kjaer Susan K SK Jensen Allan A Hogdall Claus C Lundvall Lene L Engelholm Svend Aage SA Brown Bob B Flanagan James J Metcalf Michelle D MD Siddiqui Nadeem N Sellers Thomas T Fridley Brooke B Cunningham Julie J Schildkraut Joellen J Iversen Ed E Weber Rachel P RP Berchuck Andrew A Goode Ellen E Bowtell David D DD Chenevix-Trench Georgia G deFazio Anna A Norris Murray D MD MacGregor Stuart S Haber Michelle M Henderson Michelle J MJ

Journal of the National Cancer Institute 20140623 7

<h4>Background</h4>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.<h4>Methods</h4>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. Associ ...[more]

PMID: 24957074

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Project description:BackgroundEpithelial ovarian cancer (EOC) is an aggressive disease with poor prognosis. The expression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) correlates with the malignant progression of several cancers. However, the relationship between the subcellular localization of CIAPIN1 and clinical characteristics in EOC remains unclear.MethodsImmunohistochemistry was performed to detect CIAPIN1 expression in 108 EOC tissues. CIAPIN1 expressions in eight fresh EOC tissues were detected by Western blotting. The relationship between CIAPIN1 subcellular expression and patients' clinicopathological features, including prognosis, was evaluated. Immunohistochemistry and immunofluorescence were employed to assess the CIAPIN1 subcellular localization in the EOC cell lines A2780 and HO8910. In addition, all patients were followed up to assess the prognostic value of CIAPIN1 in patients with EOC.ResultsCIAPIN1 is highly expressed in EOC, but is present at low levels in paired non-cancerous ovarian epithelial tissues. The results of Western blotting were in accordance with the immunohistochemical results. Poor differentiation of the tumors and EOC cell lines correlated with higher levels of CIAPIN1 nuclear expression. CIAPIN1 nuclear expression significantly correlated with the Federation International of Gynecology and Obstetrics (FIGO) stage and histological differentiation (P?=?0.034 and P?<?0.0001, respectively). Moreover, nuclear localization of CIAPIN1 was selected as an unfavorable prognostic factor by both univariate and multivariate analyses ( P?<?0.001). However, no significant correlations were observed between cytoplasmic localization of CIAPIN1 and clinicopathological parameters.ConclusionsCIAPIN1 might play a crucial role in the differentiation of EOC cells. Elevated expression of nuclear CIAPIN1 negatively correlated with the survival of EOC patients, suggesting that nuclear CIAPIN1 might serve as a prognostic biomarker for EOC patients.

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

Publications

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

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