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; Flemming, Claudia L.; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth Y.; Lester, Jenny; Oršulić, Sandra; Walsh, Christine; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Tōru; Yatabe, Yasushi; Pejović, Tanja; Bean, Yukie T.; Heitz, Florian; Harter, Philipp; Bois, Andreas du; Schwaab, Ira; Høgdall, Estrid; Kjær, Susanne K.; Jensen, Allan; Høgdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Robert E.; Flanagan, James M.; Metcalf, Michelle; Siddiqui, Nadeem; Sellers, Thomas A.; Fridley, Brooke L.; Cunningham, Julie M.; Schildkraut, Joellen M.; Iversen, Ed; Weber, Rachel Palmieri; Berchuck, Andrew; Goode, Ellen L.; Bowtell, David D.L.; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D.; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J.

doi:10.1093/jnci/dju149

Cited by 108 publications

(98 citation statements)

References 40 publications

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“…The correlation between gene expression and the clinicopathological characteristics was evaluated by Pearson's χ 2 test (2-sided). Expression values of a gene were dichotomized into high and low expression using the median as a cut-off in a Kaplan-Meier analysis, in accordance with previous studies (31,32). A P-value <0.05 was considered to indicate statistical significance.…”

Section: Real-time Quantitative Polymerase Chain Reaction Analysismentioning

confidence: 99%

Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer

Liu

Zou

et al. 2015

International Journal of Oncology

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Abstract. Transient receptor potential cation channel, subfamily C, member 1 (TRPC1) participates in many physiological functions but has also been implicated in cancer development. However, little is known about the role of TRPC1 in ovarian cancer (OC), including the drug resistance of these tumors. In the present study, a significant and consistent downregulation of TRPC1 in drug-resistant OC tissues/cells was determined using real-time quantitative polymerase chain reaction assays and the microarrays deposited in Oncomine and Gene Expression Omnibus (GEO) Profiles. Protein/geneprotein/gene and protein-chemical interactions indicated that TRPC1 interacts with 14 proteins/genes and 6 chemicals, all of which are involved in the regulation of drug resistance in OC. Biological process annotation of TRPC1, OC, and drug resistance indicated a role for TRPC1 in drug-resistance-related functions in OC, mainly via the cell cycle, gene expression and cell growth and cell death. Analysis of mRNA-microRNA interactions showed that 8 out of 11 major pathways enriched from 38 predominant microRNAs targeting TRPC1 were involved in the regulation of drug resistance in OC, and 8 out of these top 10 microRNAs were implicated in the drug resistance in ovarian and other cancers. In a clinical analysis using data obtained from The Cancer Genome Atlas project (TCGA) cohort on 341 OC patients, TRPC1 expression was found to differ significantly between grade 2 and grade 3 tumors, with low-level expression correlating with higher tumor grade. This is the first report to show a potential association between the downregulation of TRPC1 and both drug resistance and high histological tumor grade in OC. Our results provide the basis for further investigations of the drug-resistance-related functions of TRPC1 in OC and other forms of cancer.

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Section: Real-time Quantitative Polymerase Chain Reaction Analysismentioning

confidence: 99%

Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer

Liu

Zou

et al. 2015

International Journal of Oncology

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“…Several ABC transporters are implicated in multidrug resistance and are recognized causes for failure of cancer chemotherapy [7]- [11]. This is the case of ATP-dependent drug efflux transporter P-glycoprotein (P-gp or ABCB1) whose expression on tumor cells has been identified to be a well-recognized mechanism of cancer multidrug resistance by decreasing intracellular drug accumulation [9].…”

Section: Discussionmentioning

confidence: 99%

“…Since different individuals with a similar disease may present different responses to the same drugs due to individual aspects, it is important to understand which cellular components of tumor cells can interfere in drug response. In humans, much has been learned about ATP-binding cassette (ABC) transporters, with different cancers presenting with alterations in such cellular components, leading to failure of cancer chemotherapy [7]- [11]. Initially discovered as chemotherapeutic drug-efflux pumps, ATP-binding cassette (ABC) superfamily of transporters represents the largest family of transmembrane proteins [9].…”

Section: Introductionmentioning

confidence: 99%

Expression of Multidrug Resistance ATP-Binding Cassette (ABC) Transporters in Canine Mammary Tumors

Salgado

Nonogaki²,

Soares³

et al. 2015

ABCR

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Mammary neoplasms are the most common tumors in female dogs. They are usually treated using solely surgical mastectomy-which is recognized as unsatisfactory in many cases. Given this, the benefits of chemotherapy in dogs with mammary cancer need to be further explored. Some drugs that can be used for treating canines with mammary tumors may be substrates of uptake and/or efflux transporters such as the ATP-binding cassette (ABC) transporters. Unfortunately, very little is known regarding the pathobiology of such proteins in canine tumors, including mammary cancer. Accordingly, this study was designed to characterize the expression of ABC transporters Pglycoprotein, MRP1, and MRP2 and their relation with clinicopathologic factors in order to allow a better understanding of their influence in canine mammary cancer. P-glycoprotein was expressed in tumors from 55.8% of patients, while MRP1 and MRP2 were expressed in 37.2% and 39.5% of tumors, respectively. P-glycoprotein expression showed to be related with regional lymph node spread (P = 0.0038), as well as with tumor grade (P = 0.0353) and with a shorter survival (P = 0.0245). MRP1 revealed a strong association with a higher histological grade (P < 0.0001) and overall survival (P = 0.0002). Additionally, MRP1 was determined as prognostic indicator independent of lymph node status using Cox proportional-hazards regression multivariate analysis (P * Corresponding author. B. S. Salgado et al. 78= 0.0216). No relations between MRP2 and clinicopathologic features were observed. We have found that P-glycoprotein and MRP1 are expressed in highly aggressive canine mammary tumors and are related with poor prognosis. Our results suggest that they may play a significant role in the course of canine mammary cancer progression and be promising candidate markers for a validation study on therapy outcome.

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“…Как отмечалось выше, ранее обнаружена прямая зависимость между уровнем экспрессии АВСА9 (наряду с такими генами, как ABCA6, ABCA10, ABCB5, ABCC2, ABCC9 и ABCD2) и развитием эластической псевдосаркомы (Hendig et al, 2010) и фолликулярной лим-фомы (Baecklund et al, 2014). Суперэкспрессия ABCA9 (а также ABCA1, ABCA6 и ABCA8) значимо ассоциирована со снижением выживаемости больных серозным раком яичников (Hedditch et al, 2014). Многие авторы отмечают противоречивость полученных результатов сложивше-муся представлению о роли АВСА9 и гомологичных ему белков-транспортеров АВСА6, АВСА8, АВСА10 и ABCA1 и других, объясняемую индивидуальной вариабельно-стью их экспрессии, хотя это похоже на закономерность, которой необходимо найти объяснение.…”

Section: результаты и обсуждениеunclassified

“…Предполагается, что наряду с другими АВС-транспортерами, АВСА9 участвует в гомеостазе липидов (�e et al, 2008;Oram, Vaughan, 2006). В работе большой группы авторов (Hedditch et al, 2014) получены интересные и противоречивые результаты о том, что высокие уровни экспрессии ABCA1, ABCA6, ABCA8 и ABCA9 в первичных опухолях статистически значимо ассоциированы со снижением выживаемости больных се-розным раком яичников. При исследовании гена АВСА10, высоко гомологичного генам АВСА9 и АВСА6, показано, что его экспрессия повышена в опухолях нескольких ти-пов, в том числе в фолликулярной лимфоме (Baecklund et al, 2014), и влияет на исход заболеваний.…”

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Prediction and verification of the influence of the rs367781716 SN P on the interaction of ТАТА -binding protein with the promoter of the human АВСА9 gene

Arkova¹,

Драчкова²,

Arshinova³

et al. 2016

Vestn. VOGiS

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The high-throughput sequencing project "1 000 Genomes" made it possible to catalog and utilize genetic loci and single nucleotide polymorphisms (SNPs) in medicine. Analysis of SNP markers (significantly frequent differences of individual genomes of patients from the reference human genome) allows physicians to optimize treatment. On the other hand, tens of millions of unannotated SNPs correspond to a gigantic number of false positive (false negative) candidate SNP markers that are selected by computer methods for comparison of their frequency in patients with that in healthy people. This approach contributes to undervaluation of clinically relevant SNPs and to unnecessary computational expenses (on verifica-tion of neutral SNPs). Preclinical empirical verification of possible candidate SNP markers may eliminate neutral SNPs from the dataset. In the present study, we found, using the SNP_TATA_Comparator web service, the unannotated SNP rs367781716: the substitution of ancestral T (health) with minor C at position -37 before the transcription initiation site of the АВСА9 gene. This SNP significantly reduces affinity of TATA-binding protein (TBP) for this gene's promoter and corresponds to a defi-ciency (low protein level) of the АВСА9 gene product (the transporter ATP-binding cassette A9) in patients with the -37C allele. For preclinical empirical verification of rs367781716, we used an electrophoretic mobility shift assay (EMSA) to measure the rates of formation (ka) and decay (kd) of the complexes of TBP with an oligonucleotide matching either allele -37C or -37T of the АВСА9 gene. We found that the rate of formation (ka) of the TBP/TATA complex for the minor allele is 2.4-fold lower than that for the ancestral allele. We calculated the empirical value of the change in the equilibrium constant of dissociation (KD = kd /ka), which characterizes binding affinity of TBP for a promoter containing the ТАТА box. This empirical value matched the value predicted by SNP_ТАТА_Comparator within the margin of error of the measurements and calculations. We also determined the half-life and Gibbs free energy of the complex of TBP with the АВСА9 promo-ter. Possible phenotypic manifestations of the candidate SNP marker rs367781716 are discussed. Высокопроизводительное секвенирование ДНК, в том числе в ходе проекта «1 000 геномов», открыло возможность для учета локусов и SNPs (Single Nucleotide Polymorphism -SNP) в медицине. Это позволяет врачам улучшить лечение. Однако десяткам миллионов неаннотированных SNPs соответствует гигантское число ложноположительных (ложноотрицательных) кандидатных SNP-маркеров, отбираемых компьютерными методами для сравнения их частот у пациентов с нормой. Это способствует недооценке значимых для медицины SNPs и затратам на проверку нейтральных SNPs. Предшествующие медицинским испытаниям опыты по проверке потенциально кандидатных SNP-маркеров могут исключить нейтральные SNPs. С помощью ранее созданного Web-сервиса SNP_ TATA_ Comparator был найден неаннотированный SNP rs367781716 -замена референсного ...

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ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

Abstract: Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Cited by 108 publications

References 40 publications

Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer

Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer

Expression of Multidrug Resistance ATP-Binding Cassette (ABC) Transporters in Canine Mammary Tumors

Prediction and verification of the influence of the rs367781716 SN P on the interaction of ТАТА -binding protein with the promoter of the human АВСА9 gene

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