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Keane, S., Améen, S., Lindlöf, A. & Ejeskär, K. (2020). Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival. Cell Communication and Signaling, 18(1), Article ID 65.
Open this publication in new window or tab >>Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival
2020 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 18, no 1, article id 65Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Neuroblastoma (NB) is a childhood neural crest tumor. There are two groups of aggressive NBs, one with MYCN amplification, and another with 11q chromosomal deletion; these chromosomal aberrations are generally mutually exclusive. The DLG2 gene resides in the 11q-deleted region, thus makes it an interesting NB candidate tumor suppressor gene. METHODS: We evaluated the association of DLG2 gene expression in NB with patient outcomes, stage and MYCN status, using online microarray data combining independent NB patient data sets. Functional studies were also conducted using NB cell models and the fruit fly. RESULTS: Using the array data we concluded that higher DLG2 expression was positively correlated to patient survival. We could also see that expression of DLG2 was inversely correlated with MYCN status and tumor stage. Cell proliferation was lowered in both 11q-normal and 11q-deleted NB cells after DLG2 over expression, and increased in 11q-normal NB cells after DLG2 silencing. Higher level of DLG2 increased the percentage of cells in the G2/M phase and decreased the percentage of cells in the G1 phase. We detected increased protein levels of Cyclin A and Cyclin B in fruit fly models either over expressing dMyc or with RNAi-silenced dmDLG, indicating that both events resulted in enhanced cell cycling. Induced MYCN expression in NB cells lowered DLG2 gene expression, which was confirmed in the fly; when dMyc was over expressed, the dmDLG protein level was lowered, indicating a link between Myc over expression and low dmDLG level. CONCLUSION: We conclude that low DLG2 expression level forces cell cycle progression, and that it predicts poor NB patient survival. The low DLG2 expression level could be caused by either MYCN-amplification or 11q-deletion. Video Abstract.

Place, publisher, year, edition, pages
BioMed Central, 2020
Keywords
11q, DLG2, MAGUK, MYCN, Neuroblastoma
National Category
Medical Genetics Cancer and Oncology
Research subject
Translational Medicine TRIM; Bioinformatics
Identifiers
urn:nbn:se:his:diva-18430 (URN)10.1186/s12964-020-00553-6 (DOI)32312269 (PubMedID)2-s2.0-85083811841 (Scopus ID)
Available from: 2020-05-07 Created: 2020-05-07 Last updated: 2020-05-08Bibliographically approved
Shamloo-Dashtpagerdi, R., Lindlöf, A., Aliakbari, M. & Pirasteh-Anosheh, H. (2020). Plausible association between drought stress tolerance of barley (Hordeum vulgare L.) and programmed cell death via MC1 and TSN1 genes. Physiologia Plantarum: An International Journal for Plant Biology
Open this publication in new window or tab >>Plausible association between drought stress tolerance of barley (Hordeum vulgare L.) and programmed cell death via MC1 and TSN1 genes
2020 (English)In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054Article in journal (Refereed) Epub ahead of print
Abstract [en]

Studying the drought-responsive transcriptome is of high interest as it can serve as a blueprint for stress adaptation strategies. Despite extensive studies in this area, there are still many details to be uncovered, such as the importance of each gene involved in the stress response as well as the relationship between these genes and the physiochemical processes governing stress tolerance. This study was designed to address such important details and to gain insights into molecular responses of barley (Hordeum vulgare L.) to drought stress. To that, we combined RNA-seq data analysis with field and greenhouse drought experiments in a systems biology approach. RNA-sequence analysis identified a total of 665 differentially expressed genes (DEGs) belonging to diverse functional categories. A gene network was derived from the DEGs, which comprised of a total of 131 nodes and 257 edges. Gene network topology analysis highlighted two programmed cell death (PCD) modulating genes, MC1 (metacaspase 1) and TSN1 (Tudor-SN 1), as important (hub) genes in the predicted network. Based on the field trial, a drought-tolerant and a drought-susceptible barley genotype was identified from eight tested cultivars. Identified genotypes exhibited different physiochemical characteristics, including proline content, chlorophyll concentration, percentage of electrolyte leakage and malondialdehyde content as well as expression profiles of MC1 and TSN1 genes. Machine learning and correspondence analysis revealed a significant relationship between drought tolerance and measured characteristics in the context of PCD. Our study provides new insights which bridge barley drought tolerance to PCD through MC1 and TSN1 pathway.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
National Category
Genetics
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-18411 (URN)10.1111/ppl.13102 (DOI)000526701900001 ()32246464 (PubMedID)2-s2.0-85083302349 (Scopus ID)
Available from: 2020-04-30 Created: 2020-04-30 Last updated: 2020-05-27Bibliographically approved
Shamloo-Dashtpagerdia, R., Lindlöf, A., Niazi, A. & Pirasteh-Anosheh, H. (2019). LOS2 gene plays a potential role in barley (Hordeum vulgare L.) salinity tolerance as a hub gene. Molecular breeding, 39(8), Article ID 119.
Open this publication in new window or tab >>LOS2 gene plays a potential role in barley (Hordeum vulgare L.) salinity tolerance as a hub gene
2019 (English)In: Molecular breeding, ISSN 1380-3743, E-ISSN 1572-9788, Vol. 39, no 8, article id 119Article in journal (Refereed) Published
Abstract [en]

Understanding how plants respond to salinity stress is essential for developing tolerant genotypes, to keep human food secure since it is threaten by climate changes and increasing population worldwide. Barley (Hordeum vulgare) is a crop that possesses various salinity tolerance mechanisms that remain to be explored. In this study, data from an RNA-Seq experiment in barley was analyzed to identify changes in genome activities as well as differentially expressed genes (DEGs) in response to salinity stress. A gene network was predicted among identified DEGs and was subjected to network topology analysis, which resulted in the prediction of a hub gene, namely low expression of osmotically responsive gene 2 (LOS2). LOS2 and its two hierarchical downstream genes, salt-tolerant zinc finger (ZAT10) and ascorbate peroxidase 1 (APX1), were used in a genome-wide association (GWA) survey to confirm their importance. A field experiment was conducted to recognize susceptible and tolerant genotypes among 10 different barley genotypes based on the principle component analysis (PCA) of stress-related indices. In a separate salinity experiment, two of the genotypes were assessed to assign their physiological and biochemical responses as well as to identify expression profiles of LOS2, ZAT10, and APX1. From the results, the activity of the barley genome was significantly altered toward response to stress. In total, 5692 DEGs were identified and the gene network derived from these genes contained 131 nodes and 257 edges. The identified genotypes clearly showed the difference in water status, osmolyte accumulation, cell membrane damages, and ion homeostasis as well as in expression profiles for studied genes during salinity stress. Our results suggest that LOS2 along with the ZAT10 and APX1 genes may serve as an important part of barley salinity stress tolerance pathways. To our knowledge, this is the first report on the role(s) of LOS2 in barley salinity stress tolerance in a gene network system.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
RNA-Seq analysis, Gene network, Principle component analysis, QTL, Genome-wide association
National Category
Genetics
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-17576 (URN)10.1007/s11032-019-1026-z (DOI)000478951500002 ()2-s2.0-85070233673 (Scopus ID)
Available from: 2019-08-23 Created: 2019-08-23 Last updated: 2020-05-27Bibliographically approved
Shamloo-Dashtpagerdi, R., Razi, H., Aliakbari, M., Lindlöf, A., Ebrahimi, M. & Ebrahimie, E. (2015). A novel pairwise comparison method for in silico discovery of statistically significant cis-regulatory elements in eukaryotic promoter regions: Application to Arabidopsis: Application to Arabidopsis. Journal of Theoretical Biology, 364, 364-376
Open this publication in new window or tab >>A novel pairwise comparison method for in silico discovery of statistically significant cis-regulatory elements in eukaryotic promoter regions: Application to Arabidopsis: Application to Arabidopsis
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2015 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, Vol. 364, p. 364-376Article in journal (Refereed) Published
Abstract [en]

Cis regulatory elements (CREs), located within promoter regions, play a significant role in the blueprint for transcriptional regulation of genes. There is a growing interest to study the combinatorial nature of CREs including presence or absence of CREs, the number of occurrences of each CRE, as well as of their order and location relative to their target genes. Comparative promoter analysis has been shown to be a reliable strategy to test the significance of each component of promoter architecture. However, it remains unclear what level of difference in the number of occurrences of each CRE is of statistical significance in order to explain different expression patterns of two genes. In this study, we present a novel statistical approach for pairwise comparison of promoters of Arabidopsis genes in the context of number of occurrences of each CRE within the promoters. First, using the sample of 1000 Arabidopsis promoters, the results of the goodness of fit test and non-parametric analysis revealed that the number of occurrences of CREs in a promoter sequence is Poisson distributed. As a promoter sequence contained functional and non-functional CREs, we addressed the issue of the statistical distribution of functional CREs by analyzing the ChIP-seq datasets. The results showed that the number of occurrences of functional CREs over the genomic regions was determined as being Poisson distributed. In accordance with the obtained distribution of CREs occurrences, we suggested the Audic and Claverie (AC) test to compare two promoters based on the number of occurrences for the CREs. Superiority of the AC test over Chi-square (2 2) and Fisher’s exact tests was also shown, as the AC test was able to detect a higher number of significant CREs. The two case studies on the Arabidopsis genes were performed in order to biologically verify the pairwise test for promoter comparison. Consequently, a number of CREs with significantly different occurrences was identified between the promoters. The results of the pairwise comparative analysis together with the expression data for the studied genes revealed the biological significance of the identified CREs. 

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
CREs occurrence, Motif enrichment, Transcriptional regulation
National Category
Bioinformatics and Systems Biology
Research subject
Natural sciences; Bioinformatics
Identifiers
urn:nbn:se:his:diva-10113 (URN)10.1016/j.jtbi.2014.09.038 (DOI)000347022500037 ()25303887 (PubMedID)2-s2.0-84908323856 (Scopus ID)
Note

This publication was based on a collaboration between researchers at University of Skövde and Shiraz University, Iran.

Available from: 2014-10-23 Created: 2014-10-23 Last updated: 2020-05-27Bibliographically approved
Lindlöf, A., Chawade, A., Sikora, P. & Olsson, O. (2015). Comparative Transcriptomics of Sijung and Jumli Marshi Rice during Early Chilling Stress Imply Multiple Protective Mechanisms. PLoS ONE, 10(5), Article ID e0125385.
Open this publication in new window or tab >>Comparative Transcriptomics of Sijung and Jumli Marshi Rice during Early Chilling Stress Imply Multiple Protective Mechanisms
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0125385Article in journal (Refereed) Published
Abstract [en]

Introduction

Low temperature is one of the major environmental factors that adversely affect plant growth and yield. Many cereal crops from tropical regions, such as rice, are chilling sensitive and, therefore, are affected already at <10°C. Interestingly, it has been demonstrated that chilling susceptibility varies greatly among rice varieties, which indicates differences in the underlying molecular responses. Understanding these differences is vital for continued development of rational breeding and transgenic strategies for more tolerant varieties. Thus, in this study, we conducted a comparative global gene expression profiling analysis of the chilling tolerant varieties Sijung and Jumli Marshi (spp. Japonica) during early chilling stress (<24 h, 10°C).

Methods and Results

Global gene expression experiments were conducted with Agilent Rice Gene Expression Microarray 4x44K. The analysed results showed that there was a relatively low (percentage or number) overlap in differentially expressed genes in the two varieties and that substantially more genes were up-regulated in Jumli Marshi than in Sijung but the number of down-regulated genes were higher in Sijung. In broad GO annotation terms, the activated response pathways in Sijung and Jumli Marshi were coherent, as a majority of the genes belonged to the catalytic, transcription regulator or transporter activity categories. However, a more detailed analysis revealed essential differences. For example, in Sijung, activation of calcium and phosphorylation signaling pathways, as well as of lipid transporters and exocytosis-related proteins take place very early in the stress response. Such responses can be coupled to processes aimed at strengthening the cell wall and plasma membrane against disruption. On the contrary, in Jumli Marshi, sugar production, detoxification, ROS scavenging, protection of chloroplast translation, and plausibly the activation of the jasmonic acid pathway were the very first response activities. These can instead be coupled to detoxification processes.

Conclusions

Based on the results inferred from this study, we conclude that different, but overlapping, strategies are undertaken by the two varieties to cope with the chilling stress; in Sijung the initial molecular responses seem to be mainly targeted at strengthening the cell wall and plasma membrane, whereas in Jumli Marshi the protection of chloroplast translation and detoxification is prioritized.

Place, publisher, year, edition, pages
Public Library of Science, 2015
Keywords
cold stress, rice, Oryza sativa, microarray, data analysis, systems biology, bioinformatics
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-10985 (URN)10.1371/journal.pone.0125385 (DOI)000354545600015 ()25973918 (PubMedID)2-s2.0-84929353184 (Scopus ID)
Available from: 2015-06-02 Created: 2015-06-02 Last updated: 2020-05-27Bibliographically approved
Ulfenborg, B., Jurcevic, S., Lindelöf, A., Klinga-Levan, K. & Olsson, B. (2015). miREC: a database of miRNAs involved in the development of endometrial cancer. BMC Research Notes, 8(1), Article ID 104.
Open this publication in new window or tab >>miREC: a database of miRNAs involved in the development of endometrial cancer
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2015 (English)In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, no 1, article id 104Article in journal (Refereed) Published
Abstract [en]

Background

Endometrial cancer (EC) is the most frequently diagnosed gynecological malignancy and the fourth most common cancer diagnosis overall among women. As with many other forms of cancer, it has been shown that certain miRNAs are differentially expressed in EC and these miRNAs are believed to play important roles as regulators of processes involved in the development of the disease. With the rapidly growing number of studies of miRNA expression in EC, there is a need to organize the data, combine the findings from experimental studies of EC with information from various miRNA databases, and make the integrated information easily accessible for the EC research community.

Findings

The miREC database is an organized collection of data and information about miRNAs shown to be differentially expressed in EC. The database can be used to map connections between miRNAs and their target genes in order to identify specific miRNAs that are potentially important for the development of EC. The aim of the miREC database is to integrate all available information about miRNAs and target genes involved in the development of endometrial cancer, and to provide a comprehensive, up-to-date, and easily accessible source of knowledge regarding the role of miRNAs in the development of EC. Database URL: http://www.mirecdb.orgwebcite.

Conclusions

Several databases have been published that store information about all miRNA targets that have been predicted or experimentally verified to date. It would be a time-consuming task to navigate between these different data sources and literature to gather information about a specific disease, such as endometrial cancer. The miREC database is a specialized data repository that, in addition to miRNA target information, keeps track of the differential expression of genes and miRNAs potentially involved in endometrial cancer development. By providing flexible search functions it becomes easy to search for EC-associated genes and miRNAs from different starting points, such as differential expression and genomic loci (based on genomic aberrations).

Place, publisher, year, edition, pages
BioMed Central, 2015
Keywords
Endometrial cancer, MicroRNA, Database
National Category
Cancer and Oncology
Research subject
Medical sciences; Bioinformatics; Infection Biology
Identifiers
urn:nbn:se:his:diva-10891 (URN)10.1186/s13104-015-1052-9 (DOI)25889518 (PubMedID)2-s2.0-84940717539 (Scopus ID)
Available from: 2015-05-05 Created: 2015-05-05 Last updated: 2020-05-27Bibliographically approved
Vallabhu, R., Falck, E. & Lindlöf, A. (2014). A systems biology view of the spliceosome component Phf5a in relation to estrogen and cancer. Journal of Computer Science and Systems Biology, 7(6), 193-202
Open this publication in new window or tab >>A systems biology view of the spliceosome component Phf5a in relation to estrogen and cancer
2014 (English)In: Journal of Computer Science and Systems Biology, ISSN 0974-7230, Vol. 7, no 6, p. 193-202Article in journal (Refereed) Published
Abstract [en]

Cancer is a broad term for a wide spectrum of diseases and which involves the alteration in expression levels of several hundreds of genes. As such, the study of the disease from a systems biology point of view becomes rational, as the properties of a system as a whole may be very different from the properties of its individual components. However, understanding a network at the systems level not only requires knowledge about the components of the network, but also the interactions between them.

Here, a systems biology view of the rat PHD finger protein 5A (Phf5a) gene was attempted; a gene previously identified as aberrantly expressed in estrogen dependent endometrial adenocarcinoma tumors from both rat and human. Phf5 ais a highly conserved cysteine rich (C4HC3) zinc finger and such proteins predominantly have a role in chromatin mediated transcriptional regulation. Moreover, PHF5A is a component of the macromolecular complex spliceosome that takes part in pre-mRNA splicing and spliceosome component coding genes have previously been shown to be implicated in various cancer types and suggested to potentially be novel antitumor drugs.

To derive a systems biology view, in this study, a weighted gene network was inferred from a list of genes having correlated expression profiles to Phf5a as nodes, and common transcription factors and microRNAs regulating these genes together with annotation about biological process ontology term(s) and pathway(s) as edge weights. In the inferred network a higher weight indicates more annotation shared between two genes and, hence, the network facilitates the identification of closely interacting genes with Phf5a. The results show that highly weighted edges connect Phf5a to other spliceosome components, but also to genes involved in the metabolism of proteins, proteasome and DNA replication, repair and recombination. The results also link Phf5a to the Myc/Rb/E2F pathway, one of the central pathways associated with cancer. The proposed method for inferring a weighted gene network can easily be applied to other genes and diseases. 

Place, publisher, year, edition, pages
OMICS Publishing Group, 2014
Keywords
Cancer, Estrogen, Spliceosome, Phf5a, Systems biology, Weighted gene network
National Category
Bioinformatics and Systems Biology
Research subject
Natural sciences; Bioinformatics
Identifiers
urn:nbn:se:his:diva-10208 (URN)10.4172/jcsb.1000156 (DOI)
Available from: 2014-11-24 Created: 2014-11-20 Last updated: 2020-05-27Bibliographically approved
Shamloo-Dashtpagerdi, R., Razi, H., Lindlöf, A., Niazi, A., Dadkhodaie, A. & Ebrahimie, E. (2013). Comparative analysis of expressed sequence tags (ESTs) from Triticum monococcum shoot apical meristem at vegetative and reproductive stages. Genes and Genomics, 35(3), 365-375
Open this publication in new window or tab >>Comparative analysis of expressed sequence tags (ESTs) from Triticum monococcum shoot apical meristem at vegetative and reproductive stages
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2013 (English)In: Genes and Genomics, ISSN 1976-9571, Vol. 35, no 3, p. 365-375Article in journal (Refereed) Published
Abstract [en]

Triticum monococcum has recently drawn the attention of biologists to discover and utilize novel genes and alleles. To explore the molecular features of the genetic network governing floral transition in shoot apical meristem (SAM) of spring growth habit T. monococcum, two expressed sequence tag (EST) libraries containing 3,031 ESTs from vegetative SAM (VS) and 2,647 ESTs from early reproductive SAM (RS) were analyzed. Assembly of ESTs resulted in 2,303 unigenes for VS library (368 contigs and 1,935 singletons) and 1,890 unigenes (337 contigs and 1,553 singletons) for RS library. The 67.05 % of VS unigenes and 66.30 % of RS unigenes showed significant similarity with genes of known, putative and or unknown function, whereas the remaining 32.95 % of the VS unigenes and 33.7 % of RS unigenes displayed no significant match with the public protein database. The 1,064 and 866 unigenes of VS and RS libraries were assigned to functional categories using Pageman ontology tool. Further analysis revealed that the switch from VS to RS caused significant changes in the abundance of unigenes assigned to some functional categories. A total of 37 genes were identified which were significantly differentially expressed between vegetative and reproductive stages of T. monococcum SAM. Investigation of the differentially expressed genes revealed the importance of the genes involved in energy metabolism, ubiquitin/26S proteasome system, polyamines biosynthesis and signaling of reactive oxygen species in SAM differentiation towards floral transition in T. monococcum.

Place, publisher, year, edition, pages
The Genetics Society of Korea, 2013
Keywords
Triticum monococcum, Shoot apical meristem, Floral transition, EST analysis, Functional annotation
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-8576 (URN)10.1007/s13258-013-0091-7 (DOI)000319614200010 ()2-s2.0-84878757156 (Scopus ID)
Available from: 2013-10-28 Created: 2013-10-28 Last updated: 2020-05-27Bibliographically approved
Chawade, A., Lindlöf, A., Olsson, B. & Olsson, O. (2013). Global expression profiling of low temperature induced genes in the chilling tolerant japonica rice jumli marshi. PLoS ONE, 8(12), e81729, Article ID e81729.
Open this publication in new window or tab >>Global expression profiling of low temperature induced genes in the chilling tolerant japonica rice jumli marshi
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81729-, article id e81729Article in journal (Refereed) Published
Abstract [en]

Low temperature is a key factor that limits growth and productivity of many important agronomical crops worldwide. Rice (Oryza sativa L.) is negatively affected already at temperatures below +10°C and is therefore denoted as chilling sensitive. However, chilling tolerant rice cultivars exist and can be commercially cultivated at altitudes up to 3,050 meters with temperatures reaching as low as +4°C. In this work, the global transcriptional response to cold stress (+4°C) was studied in the Nepalese highland variety Jumli Marshi (spp. japonica) and 4,636 genes were identified as significantly differentially expressed within 24 hours of cold stress. Comparison with previously published microarray data from one chilling tolerant and two sensitive rice cultivars identified 182 genes differentially expressed (DE) upon cold stress in all four rice cultivars and 511 genes DE only in the chilling tolerant rice. Promoter analysis of the 182 genes suggests a complex cross-talk between ABRE and CBF regulons. Promoter analysis of the 511 genes identified over-represented ABRE motifs but not DRE motifs, suggesting a role for ABA signaling in cold tolerance. Moreover, 2,101 genes were DE in Jumli Marshi alone. By chromosomal localization analysis, 473 of these cold responsive genes were located within 13 different QTLs previously identified as cold associated.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-8711 (URN)10.1371/journal.pone.0081729 (DOI)000328731800024 ()24349120 (PubMedID)2-s2.0-84892623587 (Scopus ID)
Available from: 2014-01-02 Created: 2014-01-02 Last updated: 2020-05-27Bibliographically approved
Wegman, P., Göthlin Eremo, A., Lindlöf, A., Karlsson, M., Stål, O. & Wingren, S. (2011). Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen. International Journal of Oncology, 38(4), 1145-1151
Open this publication in new window or tab >>Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen
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2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 4, p. 1145-1151Article in journal (Refereed) Published
Abstract [en]

Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter II in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 post-menopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters I.3, II and I.7 of the aromatase gene of which promoter I.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter I.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

Place, publisher, year, edition, pages
Spandidos Publications Ltd., 2011
Keywords
breast cancer, forkhead box L2, aromatase, tissue specific promoters, in silico
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5153 (URN)10.3892/ijo.2011.923 (DOI)000288581100027 ()21271216 (PubMedID)2-s2.0-79952329924 (Scopus ID)
Available from: 2011-06-28 Created: 2011-06-28 Last updated: 2020-05-27Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1837-429x

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