Publications by authors named "Igor Girault"

10 Publications

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The Jurassic magmatism of the Demerara Plateau (offshore French Guiana) as a remnant of the Sierra Leone hotspot during the Atlantic rifting.

Sci Rep 2020 05 4;10(1):7486. Epub 2020 May 4.

Anton de Kom University of Suriname, Paramaribo, SA, Suriname.

We report the discovery of 173.4 Ma hotspot-related magmatic rocks in the basement of the Demerara Plateau, offshore French Guiana and Suriname. According to plate reconstructions, a single hotspot may be responsible for the magmatic formation of (1) both the Demerara Plateau (between 180 and 170 Ma) and the Guinea Plateau (circa 165 Ma) during the end of the Jurassic rifting of the Central Atlantic; (2) both Sierra Leone and Ceara Rises (mainly from 76 to 68 Ma) during the upper Cretaceous oceanic spreading of the Equatorial Atlantic ocean; (3) the Bathymetrists seamount chain since the upper Cretaceous. The present-day location of the inferred Sierra Leone hotspot should be 100 km west of the Knipovich Seamount.
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http://dx.doi.org/10.1038/s41598-020-64333-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198611PMC
May 2020

Role of estrogen receptor alpha transcriptional coregulators in tamoxifen resistance in breast cancer.

Maturitas 2006 Jul 5;54(4):342-51. Epub 2006 Jul 5.

Centre René Huguenin, FNCLCC, INSERM, U735, F-92210, St Cloud, France.

Tamoxifen is the endocrine agent most commonly used at all stages of breast cancer. Estrogen receptor (ER) alpha, which belongs to the superfamily of nuclear receptors, has been used to identify breast cancer patients who are likely to respond to tamoxifen, but resistance nonetheless occurs in 30-50% of treated ER alpha-positive breast cancer patients. The antiproliferative activity of tamoxifen, relying primarily on its ability to compete with estrogen for the ER alpha ligand binding site in breast tumor tissue, hypotheses forwarded to explain treatment failure include: (1) the existence of a second estrogen receptor (ER beta), (2) an imbalance in estrogen biosynthesis and catabolism, (3) altered bioavailability of tamoxifen, (4) altered cellular trafficking of ER alpha, (5) non genomic effects of ER alpha, directly interacting with several signal transduction pathways, and (6) transcriptional dysregulation of ER alpha target genes, which may involve both genomic (ERE alteration) and non genomic alterations. A first non genomic alteration involves the regulation of ER alpha activity by its phosphorylation mediated by growth factors-kinases signaling pathways. A second non genomic alteration, which is the purpose of this review, involves regulatory factors (coregulators) known as coactivators and corepressors, which activate (or repress) the transcription of ER alpha-responsive genes. The regulation process involves both chromatin remodeling and ER alpha interaction with the transcriptional machinery. Thus, dysregulated expression (coactivator overexpression or corepressor underexpression) and/or mutation of these coregulators is thought to impair the action of tamoxifen. Many altered pathways may account for tamoxifen resistance which may be best studied by multigene approaches.
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http://dx.doi.org/10.1016/j.maturitas.2006.06.003DOI Listing
July 2006

Simultaneous measurement of 23 isoforms from the human cytochrome P450 families 1 to 3 by quantitative reverse transcriptase-polymerase chain reaction.

Drug Metab Dispos 2005 Dec 31;33(12):1803-10. Epub 2005 Aug 31.

Société Biopredic International, Rennes, France.

Drug metabolism in humans is essentially performed by three cytochrome P450 (P450) families (1 to 3), including 23 isoforms. The expression of these P450s is highly variable, and the rate and nature of the metabolites produced depend on the nature and the concentration of individual isoforms. P450 expression pattern is therefore a necessary tool to evaluate the effects of a given drug on P450 expression, its potential toxicity, and eventual interference with other drugs administered concomitantly. This pattern provides a general outline of the induction/repression effects of drugs leading to further mechanistic studies. A real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to evaluate the overall P450 expression pattern and measure human CYP1 to CYP3 mRNAs involved in drug metabolism. Our RT-PCR-based P450 mRNA assay enables us to quantify P450s rapidly with high specificity, a single annealing temperature, and low amounts of biological sample. All 23 single assays were validated by assessing the effects (induction or repression) of known inducers (ethanol, 3-methylcholanthrene, rifampicin, dexamethasone, phenobarbital) on P450 expression in human primary hepatocytes. Since this method may be used to determine human P450 expression in any human tissue or cell culture, it is a valuable tool for reliable prediction of drug safety, drug toxicity, and drug-drug interference.
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http://dx.doi.org/10.1124/dmd.105.005173DOI Listing
December 2005

Identification of a three-gene expression signature of poor-prognosis breast carcinoma.

Mol Cancer 2004 Dec 20;3(1):37. Epub 2004 Dec 20.

Laboratoire d'Oncogénétique-INSERM E0017, Centre René Huguenin, St-Cloud, France.

Background: The clinical course of breast cancer is difficult to predict on the basis of established clinical and pathological prognostic criteria. Given the genetic complexity of breast carcinomas, it is not surprising that correlations with individual genetic abnormalities have also been disappointing. The use of gene expression profiles could result in more accurate and objective prognostication.

Results: To this end, we used real-time quantitative RT-PCR assays to quantify the mRNA expression of a large panel (n = 47) of genes previously identified as candidate prognostic molecular markers in a series of 100 ERalpha-positive breast tumor samples from patients with known long-term follow-up. We identified a three-gene expression signature (BRCA2, DNMT3B and CCNE1) as an independent prognostic marker (P = 0.007 by univariate analysis; P = 0.006 by multivariate analysis). This "poor prognosis" signature was then tested on an independent panel of ERalpha-positive breast tumors from a well-defined cohort of 104 postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone: although this "poor prognosis" signature was associated with shorter relapse-free survival in univariate analysis (P = 0.029), it did not persist as an independent prognostic factor in multivariate analysis (P = 0.27).

Conclusion: Our results confirm the value of gene expression signatures in predicting the outcome of breast cancer.
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http://dx.doi.org/10.1186/1476-4598-3-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC544833PMC
December 2004

Altered expression pattern of alternatively spliced estrogen receptor beta transcripts in breast carcinoma.

Cancer Lett 2004 Nov;215(1):101-12

Laboratoire d'Oncogénétique--INSERM E0017, Centre Rene Huguenin, F-92211 St-Cloud, France.

Dysregulation of total estrogen receptor beta (ERbeta) expression has been implicated in breast tumorigenesis. The ERbeta gene yields five exon 8 alternatively spliced transcripts (ERbeta1-5), which encode proteins with different C-terminal amino acids. Individual expression analysis of these transcripts may provide new insights into estrogen signaling in breast cancer. We measured mRNA levels of total ERbeta and its five isoforms in normal tissues, breast carcinomas from post-menopausal patients, and breast cancer cell lines by means of real-time reverse transcription-polymerase chain reaction and fluorescent fragment analysis. In various normal human tissues, ERbeta1-5 isoforms displayed different qualitative and quantitative expression patterns that were consistent with previous reports. Total ERbeta mRNA levels were significantly lower in breast tumors than in normal breast tissues (38-fold lower, P < 0.001), mainly due to lower expression of ERbeta1 and ERbeta2 (ERbeta5 expression was similar in the two tissue types). This altered expression pattern of ERbeta isoforms in breast cancer should be taken into account in future ERbeta-based clinical applications.
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http://dx.doi.org/10.1016/j.canlet.2004.05.006DOI Listing
November 2004

Evaluation of mRNA expression of estrogen receptor beta and its isoforms in human normal and neoplastic endometrium.

Int J Cancer 2004 Jul;110(6):783-7

Second Department of Gynecology, Prof. F. Skubiszewski University School of Medicine, Jaczewskiego 8 St., 20-090 Lublin, Poland.

Endometrial cancer is well known to be estrogen-dependent. Two estrogen receptor types, ERalpha and ERbeta, are major mediators of a diversity of biologic functions of estrogen and play an important role in estrogen-dependent tissues and cancers. Cloning of ERbeta was followed by the discovery of a variety of its isoforms. Using real-time RT-PCR, the relative expression levels of ERbeta1, ERbeta2 (ERbetacx), ERbeta3, ERbeta4 and ERbeta5 were studied. We observed coexpression of ERbeta isoforms in the endometrium and upregulation of the ERbeta5 transcript in malignant endometrium. We also observed downregulation of ERbeta2Delta5 transcript in neoplastic endometrium, using a semiquantitative method. Our results suggest that analyzing the changes in ERbeta and its isoforms may be important in the diagnosis, prognosis and treatment of endometrial cancer.
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http://dx.doi.org/10.1002/ijc.20224DOI Listing
July 2004

Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma.

Breast Cancer Res 2004 26;6(3):R252-63. Epub 2004 Mar 26.

Laboratoire d'Oncogénétique - INSERM E0017, Centre René Huguenin, St-Cloud, France.

Introduction: Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability.

Methods: To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERalpha)-negative and ERalpha-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERalpha-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone.

Results: Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERalpha-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERalpha-positive breast tumors than in ERalpha-negative breast tumors. In the 97 ERalpha-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERalpha-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013).

Conclusions: Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness.
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http://dx.doi.org/10.1186/bcr784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC400681PMC
July 2004

Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression.

Carcinogenesis 2004 Mar 21;25(3):405-11. Epub 2003 Nov 21.

Laboratoire d'Oncogénétique-INSERM E0017, Centre René Huguenin, St-Cloud, France.

The PEA3/E1AF/ETV4 gene encodes an Ets-related transcription factor that is expressed in the epithelial cells of the mammary gland. Previous reports have shown that PEA3 can up-regulate promoter activities of many genes associated with tumorigenesis. A significant fraction of those encode matrix metalloproteinases (MMP genes) required for degradation of the extracellular matrix. To better obtain a molecular characterization of PEA3 expression in sporadic breast cancer, we quantified PEA3 mRNA by means of real-time reverse transcriptase-polymerase chain reaction assay in a large series of human primary breast tumors. PEA3 expression showed wide variations in tumor tissues, being under-expressed in 30 of 130 (23.1%) and over-expressed in 18 of 130 (13.8%) compared with normal breast tissues. High PEA3 mRNA levels correlated significantly with Scarff-Bloom-Richardson histopathological grade III (P = 0.018) but not with poor prognosis, suggesting that PEA3 is a marker of tumor aggressiveness rather than a prognostic factor in human breast cancer. We also observed positive links between the expression of PEA3 and those of MKI67 and ERBB2 (P = 0.034 and P = 0.045, respectively) and an inverse relationship with ERalpha (P = 0.0016). Our results do not support recent findings suggesting that PEA3 could be a tumor-suppressor gene that can act therapeutically in ERBB2 over-expressed tumors. Our results also suggest major roles of the MMP2, NRG1 and CGB genes (which encode type I gelatinase, heregulin and human chorionic gonadotropin beta subunit, respectively) in the PEA3 pathway dysregulation observed in breast cancer. Taken together, the data confirm the role of the PEA3 gene in breast tumorigenesis, and suggest the existence of numerous other still unknown genes transactivated by the PEA3 transcription factor.
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http://dx.doi.org/10.1093/carcin/bgh024DOI Listing
March 2004

Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas.

Clin Cancer Res 2003 Oct;9(12):4415-22

Laboratoire d'Oncogénétique-Institut National de la Santé et de la Recherche Médicale E0017 Centre René Huguenin, F-92211 St-Cloud, France.

Purpose: Three genes, namely DNA methyltransferase (DNMT) 1, DNMT3A, and DNMT3B, coding for DNMTs that affect promoter methylation status are thought to play an important role in the development of cancers. Little is known of the biological and clinical significance of these genes in human breast cancer.

Experimental Design: We used real-time reverse transcription-PCR assays to quantify the mRNA expression of the three DNMT genes in a series of 130 breast cancer patients. We also sought relationships between mRNA levels of the DNMTs and those of 20 target genes involved in the DNMT pathway (subgroup of 46 breast tumors).

Results: The DNMT3B gene showed the highest range of expression (81.8 compared with 16.6 and 14 for DNMT1 and DNMT3A, respectively). DNMT3B was overexpressed in 30% of the patients (5.4 and 3.1% for DNMT1 and DNMT3A, respectively). DNMT3B overexpression was significantly related to Scarff, Bloom, and Richardson histopathological grade III (P = 0.002), ERalpha negativity (P = 0.0015), and strong MKI67 expression (P = 3 x 10(-6)). In univariate analysis, DNMT3B overexpression was associated with poor relapse-free survival in the subgroup of patients who received adjuvant hormone therapy (with or without chemotherapy; P = 0.0064). Although the poor prognosis associated with DNMT3B overexpression was confirmed by univariate analysis in an independent series of 98 postmenopausal women exclusively treated with adjuvant tamoxifen therapy (P = 0.0036), DNMT3B expression status did not persist as an independent prognostic factor in multivariate analysis.

Conclusions: Although we failed to identify underexpression of specific target genes associated with DNMT increasing expression, the frequent overexpression of DNMT3B in this breast tumor series points to DNMT3B as a potential new therapeutic target in breast cancer.
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October 2003

Expression analysis of estrogen receptor alpha coregulators in breast carcinoma: evidence that NCOR1 expression is predictive of the response to tamoxifen.

Clin Cancer Res 2003 Apr;9(4):1259-66

Laboratoire d'Oncogénétique, Institut National de la Santé et de la Recherche Médicale E0017, Centre René Huguenin, F-92211 St-Cloud, France.

Purpose: Dysregulated expression of steroid receptor transcriptional coactivators and corepressors has been implicated in tamoxifen resistance, especially in estrogen receptor (ER) alpha-positive breast cancer patients. Therefore, expression analysis of these ERalpha coregulators may identify new predictors of the response to tamoxifen treatment.

Experimental Design: We measured mRNA levels of 16 coactivator and 11 corepressor genes with a real-time quantitative reverse transcription-PCR method in 14 ERalpha-positive breast tumors. Three selected coactivator genes (TIF2, AIB1, and GCN5L2) and two corepressor genes (NCOR1 and MTA1L1) were additionally investigated in a well-characterized series of ERalpha-positive unilateral invasive primary breast tumors from 99 postmenopausal patients who only received tamoxifen as adjuvant hormone therapy after primary surgery. We sought relationships between mRNA levels of the coregulators and those of molecular markers, including ERalpha, ERbeta, CCND1, and ERBB2.

Results: ERalpha coregulator expression was unrelated to age, histological grade, lymph node status, and macroscopic tumor size. The relationship between mRNA expression of the coregulators, and ERalpha and beta only showed a significant positive correlation between GCN5L2 and ERalpha (P = 0.015). mRNA levels of CCND1 correlated with those of all of the coregulators studied (P < 0.05 or trend), whereas ERBB2 mRNA levels only correlated with AIB1 mRNA levels (P = 0.011). Low NCOR1 expression (versus intermediate and high) was associated with significantly shorter relapse-free survival (log-rank test; P = 0.0076). The prognostic significance of low NCOR1 expression persisted in Cox multivariate regression analysis (P = 0.043).

Conclusions: These findings point to NCOR1 as a promising independent predictor of tamoxifen resistance in patients with ERalpha-positive breast tumors.
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April 2003