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

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 ERα-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 ERα-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

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

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 (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-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 ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-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 ERα-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

Marqueurs moléculaires impliqués dans la résistance au tamoxifène dans le cancer du sein

Dans le cancer du sein, l'action des estrogènes (E) médiée par son récepteur a, est bien documentée. Après un premier temps de réponse au cours d'un traitement par le tamoxifène (Tam), une résistance pharmacologique peut survenir. Nous avons étudié l'expression de gènes pouvant être impliqués dans cette résistance. Parmi des corégulateurs transcriptionnels, seul le corépresseur NCOR1 a conservé son potentiel prédictif. L'étude des DNMTs a révélé une association uniquement entre l'expression de DNMT3B et un mauvais pronostic. L'étude de l'aromatase n'a pas permis d'établir de relation avec un mécanisme de résistance. Enfin, nous avons identifié le gène NAT1, dont la sur-expression s'est révélée associée à une survie favorable. La résistance au Tam apparaît donc multifactorielle, impliquant diverses voies métaboliques dont la compréhension permet la mise en place d'outils diagnostics et/ou thérapeutiques visant à diminuer la sélection de cellules tumorales résistantes.In breast cancer, estrogens (E) action, mediated by its receptor a, is well documented. After a first period of response during a treatment by the tamoxifen (Tam), a pharmacological resistance may occur. We studied the expression of several genes which may be involved in Tam resistance. Among transcriptional coregulators, the corepressor NCOR1 was the only gene associated with a predictive value. The study of DNMTs genes only revealed a relationship between DNMT3B expression and markers of poor pronostic. The expression of aromatase was not associated with Tam resistance. Finally, we identified the NAT1 gene which expression was linked with a good outcome. In conclusion, the Tam resistance appears to involve several metabolic pathways. A better understanding of these pathways may lead to the use of new diagnostics markers or treatments in order to overcome the Tam resistance.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Campagne DRADEM – Juillet 2016 - Rapport scientifique

La campagne DRADEM s’est déroulée du 9 au 21 Juillet 2016 à bord du Pourquoi Pas ?, dans les zones économique exclusives du Suriname et de la Guyane. Cette campagne s’inscrit dans un programme d’étude géologique du plateau de Demerara, dans la suite des campagnes GUYAPLAC (2003), IGUANES (2013), et avant MARGATS (2016). Les objectifs de la campagne DRADEM étaient de cartographier la pente continentale de la marge transformante bordant au Nord le Plateau de Demerara, et d’échantillonner par dragage les roches qui y affleurent.La bathymétrie de la totalité de la pente continentale et une partie de la bordure du plateau ont été cartographiées, confirmant la segmentation de cette marge en trois parties avec des caractéristiques morphologiques très différentes. Deux probables volcans de boue ont été identifiés, l’un sur la bordure nord du plateau, l’autre dans la partie distale du cône sous-marin de l’Orénoque.Douze dragages ont été réalisés entre 4700 et 3500 m de profondeur. Quatre dragues n’ont pas remonté d’échantillons. Les huit autres ont remonté des quantités variables de roches, très souvent encroûtées, mais à chaque fois de natures différentes : sédiments (brèche, grès grossiers, grès à plantes, grès coquillers, marne calcaire), roches grenues et métamorphiques (dont mylonites). Les déterminations lithologiques sont basées sur l’observation macroscopique de roches souvent altérées, et restent bien sûr à confirmer par les études à terre ; mais dans tous les cas ces roches pour la plupart inconnues dans ce secteur vont radicalement modifier notre compréhension de la structure et de l’évolution de cette marge. Elles mettent en évidence des mouvements verticaux importants qui ont ramené à l’affleurement des roches formées en profondeur

DRADEM campaign - 2016 July - Scientific report

The DRADEM campaign was performed from July 9th to 21th 2016 on board the Pourquoi Pas?, in the Exclusive Economic Zones of Suriname and French Guyana. This campaign belongs to a program dedicated to geological investigations of the Demerara plateau, following the GUYAPLAC (2003) and IGUANES (2013) campaigns, and before the MARGATS campaign (2016). The aims of the DRADEM campaign were to map the continental slope of the transform margin north of the Demerara plateau, and to dredge the rocks outcropping in the slope.We completed the bathymetric mapping of the continental slope, including part of the edged of the Demerara plateau. These new bathymetric data confirm the segmentation of the transform margin in three parts with very different morphologies. In addition, two circular structures were interpreted as mud volcanoes, one on the northern edge of the plateau, the other one in the distal part of the Orinoco deep sea fan.Twelve dredges were performed between 4700 and 3500 m depths. Four from these twelve did not recovered rocks. The eight others brought back variables amounts of rocks, often encrusted, but of various natures: sediments (breccia, coarse sandstones, sandstones with plants debris, sandstones with shells, clayey ooze), micro-granular rocks and metamorphic rocks (including mylonite). The nature of the rocks was determined from macroscopic observation of the rocks, which are currently altered. Of course, these determinations need to be validated and specified by onshore further studies. Anyway, most of these rocks were previously unknown in this area, and they will strongly influence our understanding of the structure and evolution of this margin. They evidence huge vertical displacements that brought back to the surface some of these rocks that formed in a deep setting

DRADEM campaign - 2016 July - Scientific report

The DRADEM campaign was performed from July 9th to 21th 2016 on board the Pourquoi Pas?, in the Exclusive Economic Zones of Suriname and French Guyana. This campaign belongs to a program dedicated to geological investigations of the Demerara plateau, following the GUYAPLAC (2003) and IGUANES (2013) campaigns, and before the MARGATS campaign (2016). The aims of the DRADEM campaign were to map the continental slope of the transform margin north of the Demerara plateau, and to dredge the rocks outcropping in the slope.We completed the bathymetric mapping of the continental slope, including part of the edged of the Demerara plateau. These new bathymetric data confirm the segmentation of the transform margin in three parts with very different morphologies. In addition, two circular structures were interpreted as mud volcanoes, one on the northern edge of the plateau, the other one in the distal part of the Orinoco deep sea fan.Twelve dredges were performed between 4700 and 3500 m depths. Four from these twelve did not recovered rocks. The eight others brought back variables amounts of rocks, often encrusted, but of various natures: sediments (breccia, coarse sandstones, sandstones with plants debris, sandstones with shells, clayey ooze), micro-granular rocks and metamorphic rocks (including mylonite). The nature of the rocks was determined from macroscopic observation of the rocks, which are currently altered. Of course, these determinations need to be validated and specified by onshore further studies. Anyway, most of these rocks were previously unknown in this area, and they will strongly influence our understanding of the structure and evolution of this margin. They evidence huge vertical displacements that brought back to the surface some of these rocks that formed in a deep setting

DRADEM campaign - 2016 July - Scientific report

The DRADEM campaign was performed from July 9th to 21th 2016 on board the Pourquoi Pas?, in the Exclusive Economic Zones of Suriname and French Guyana. This campaign belongs to a program dedicated to geological investigations of the Demerara plateau, following the GUYAPLAC (2003) and IGUANES (2013) campaigns, and before the MARGATS campaign (2016). The aims of the DRADEM campaign were to map the continental slope of the transform margin north of the Demerara plateau, and to dredge the rocks outcropping in the slope.We completed the bathymetric mapping of the continental slope, including part of the edged of the Demerara plateau. These new bathymetric data confirm the segmentation of the transform margin in three parts with very different morphologies. In addition, two circular structures were interpreted as mud volcanoes, one on the northern edge of the plateau, the other one in the distal part of the Orinoco deep sea fan.Twelve dredges were performed between 4700 and 3500 m depths. Four from these twelve did not recovered rocks. The eight others brought back variables amounts of rocks, often encrusted, but of various natures: sediments (breccia, coarse sandstones, sandstones with plants debris, sandstones with shells, clayey ooze), micro-granular rocks and metamorphic rocks (including mylonite). The nature of the rocks was determined from macroscopic observation of the rocks, which are currently altered. Of course, these determinations need to be validated and specified by onshore further studies. Anyway, most of these rocks were previously unknown in this area, and they will strongly influence our understanding of the structure and evolution of this margin. They evidence huge vertical displacements that brought back to the surface some of these rocks that formed in a deep setting