A Puisieux

Publications (46)264.86 Total impact

• Source

  Available from: Caroline Moyret-Lalle

  Dataset: PDF Dicer and breast cancer 2009

  C Moyret-Lalle, C Lasset, A-S Ay, R Rimokh, D G Cox, I Mikaelian, S Chabaud, C Venoux, G Grelier, S Léon-Goddard, I Treilleux, A Puisieux, N Voirin
• Source

  Available from: Alexia De Gasperis

  Article: TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression.

  C Ruptier, A De Gaspéris, S Ansieau, A Granjon, P Tanière, I Lafosse, H Shi, A Petitjean, E Taranchon-Clermont, V Tribollet, T Voeltzel, J-Y Scoazec, V Maguer-Satta, A Puisieux, P Hainaut, C Cavard, C Caron de Fromentel
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  ABSTRACT: The ΔNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. ΔNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominant-negative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of ΔNp63 overexpression is not fully understood. Here, we show that the expression of ΔNp63 is regulated by the Wnt/β-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that ΔNp63 and β-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the β-catenin pathway may contribute to overexpression of ΔNp63 during tumour progression, in a cell type-specific manner.
  Oncogene 06/2011; 30(46):4656-65. · 6.37 Impact Factor
• Source

  Available from: Shlomi (Shalom) Madar

  Article: Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells.

  I Kogan-Sakin, Y Tabach, Y Buganim, A Molchadsky, H Solomon, S Madar, I Kamer, P Stambolsky, A Shelly, N Goldfinger, S Valsesia-Wittmann, A Puisieux, A Zundelevich, E N Gal-Yam, C Avivi, I Barshack, M Brait, D Sidransky, E Domany, V Rotter
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  ABSTRACT: A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53(R175H), was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53(R175H) mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53(R175H) mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.
  Cell death and differentiation 02/2011; 18(2):271-81. · 8.24 Impact Factor
• Source

  Available from: Caroline Moyret-Lalle

  Article: Complexity in the regulation of Dicer expression: Dicer variant proteins are differentially expressed in epithelial and mesenchymal breast cancer cells and decreased during EMT.

  G W Hinkal, G Grelier, A Puisieux, C Moyret-Lalle
  British Journal of Cancer 01/2011; 104(2):387-8. · 5.04 Impact Factor
• Article: Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

  I Kogan-Sakin, Y Tabach, Y Buganim, A Molchadsky, H Solomon, S Madar, I Kamer, P Stambolsky, A Shelly, N Goldfinger, S Valsesia-Wittmann, A Puisieux, A Zundelevich, E N Gal-Yam, C Avivi, I Barshack, M Brait, D Sidransky, E Domany, V Rotter
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  ABSTRACT: A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 ‘gain of function’ (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53R175H mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53R175H, was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial–mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53R175H mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53R175H mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.Keywords: p53; Twist1; prostate
  Cell Death and Differentiation 08/2010; 18(2):271-281. · 8.85 Impact Factor
• Article: TWISTing an embryonic transcription factor into an oncoprotein.

  S Ansieau, A-P Morel, G Hinkal, J Bastid, A Puisieux
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  ABSTRACT: Over the past decade, the reactivation of TWIST embryonic transcription factors has been described as a frequent event and a marker of poor prognosis in an impressive array of human cancers. Growing evidence now supports the premise that these cancers hijack TWIST's embryonic functions, granting oncogenic and metastatic properties. In this review, we report on the history and recent breakthroughs in understanding TWIST protein functions and the emerging role of the associated epithelial-mesenchymal transition (EMT) in tumorigenesis. We then broaden the discussion to address the general contribution of reactivating embryonic programs in cancerogenesis.
  Oncogene 04/2010; 29(22):3173-84. · 6.37 Impact Factor
• Article: Revisiting the canonical tumour progression model.

  S Ansieau, G Hinkal, A-P Morel, A Puisieux
  Pathologie Biologie 03/2010; 59(6):294-7. · 1.53 Impact Factor
• Article: [Role of the epithelial-mesenchymal transition during tumor progression].

  S Ansieau, C Caron de Fromentel, J Bastid, A-P Morel, A Puisieux
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  ABSTRACT: The epithelial-mesenchymal transition (EMT) is a morphogenetic program that converts epithelial into mesenchymal cells during the embryonic development. This mechanism is frequently reactivated during tumor progression and provides cells with motility and invasive capabilities favoring the metastatic dissemination from epithelial tumors. Various EMT-inducing transcription factors, such as the TWIST proteins, were also shown to inhibit oncogene-induced fail-safe programs (senescence and apoptosis), thereby promoting the progression from benign to malignant stages. Altogether, these observations suggest that EMT could play an important role in favoring both tumor development and metastatic dissemination.
  Bulletin du cancer 12/2009; 97(1):7-15. · 0.67 Impact Factor
• Source

  Available from: Caroline Moyret-Lalle

  Article: Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype.

  G Grelier, N Voirin, A-S Ay, D G Cox, S Chabaud, I Treilleux, S Léon-Goddard, R Rimokh, I Mikaelian, C Venoux, A Puisieux, C Lasset, C Moyret-Lalle
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  ABSTRACT: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer. In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular models, and in two well-characterised sets of breast carcinoma samples obtained from patients with long-term follow-up using tissue microarrays and quantitative reverse transcription-PCR. We have found that Dicer protein expression is significantly associated with hormone receptor status and cancer subtype in breast tumours (ER P=0.008; PR P=0.019; cancer subtype P=0.023, luminal A P=0.0174). Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease (hazard ratio=3.36, P=0.0032). In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggest that the downregulation of Dicer expression may be related to the metastatic spread of tumours. Assessment of Dicer expression may facilitate prediction of distant metastases for patients suffering from breast cancer.
  British Journal of Cancer 09/2009; 101(4):673-83. · 5.04 Impact Factor
• Article: Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype

  G Grelier, N Voirin, A-S Ay, D G Cox, S Chabaud, I Treilleux, S L|[eacute]|on-Goddard, R Rimokh, I Mikaelian, C Venoux, A Puisieux, C Lasset, C Moyret-Lalle
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  ABSTRACT: Background: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer.
  British Journal of Cancer 08/2009; 101(4):673-683. · 5.04 Impact Factor
• Article: Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles.

  F Bertucci, B Orsetti, V Nègre, P Finetti, C Rougé, J-C Ahomadegbe, F Bibeau, M-C Mathieu, I Treilleux, J Jacquemier, L Ursule, A Martinec, Q Wang, J Bénard, A Puisieux, D Birnbaum, C Theillet
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  ABSTRACT: Invasive ductal carcinomas (IDCs) and invasive lobular carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data suggest biological differences, but little is known about the molecular alterations involved in ILCs. We undertook a comparative large-scale study by both array-compared genomic hybridization and cDNA microarray of a set of 50 breast tumors (21 classic ILCs and 29 IDCs) selected on homogeneous histoclinical criteria. Results were validated on independent tumor sets, as well as by quantitative RT-PCR. ILCs and IDCs presented differences at both the genomic and expression levels with ILCs being less rearranged and heterogeneous than IDCs. Supervised analysis defined a 75-BACs signature discriminating accurately ILCs from IDCs. Expression profiles identified two subgroups of ILCs: typical ILCs ( approximately 50%), which were homogeneous and displayed a normal-like molecular pattern, and atypical ILCs, more heterogeneous with features intermediate between ILCs and IDCs. Supervised analysis identified a 75-gene expression signature that discriminated ILCs from IDCs, with many genes involved in cell adhesion, motility, apoptosis, protein folding, extracellular matrix and protein phosphorylation. Although ILCs and IDCs share common alterations, our data show that ILCs and IDCs could be distinguished on the basis of their genomic and expression profiles suggesting that they evolve along distinct genetic pathways.
  Oncogene 06/2008; 27(40):5359-72. · 6.37 Impact Factor
• Article: Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with DeltaNp73.

  A Petitjean, C Ruptier, V Tribollet, A Hautefeuille, F Chardon, C Cavard, A Puisieux, P Hainaut, C Caron de Fromentel
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  ABSTRACT: TP63, a member of the TP53 gene family, encodes two groups of three isoforms (alpha, beta and gamma). The TAp63 isoforms act as transcription factors. The DeltaNp63 isoforms lack the main transcription activation domain and act as dominant-negative inhibitors of transactivation (TA) isoforms. To clarify the role of these isoforms and to better understand their functional overlap with p53, we ectopically expressed each p63 isoform in the p53-null hepatocellular carcinoma cell line Hep3B. All TA isoforms, as well as DeltaNp63alpha, had a half-life of <1 h when transiently expressed and were degraded by the proteasome pathway. The most stable form was DeltaNp63gamma, with a half-life of >8 h. As expected, TA isoforms differed in their transcriptional activities toward genes regulated by p53, TAp63gamma being the most active form. In contrast, DeltaNp63 isoforms were transcriptionally inactive on genes studied and inhibited TA isoforms in a dose-dependent manner. When stably expressed in polyclonal cell populations, TAp63beta and gamma isoforms were undetectable. However, when treated with doxorubicin (DOX), p63 proteins rapidly accumulated in the cells. This stabilization was associated with an increase in phosphorylation. Strikingly, in DOX-treated polyclonal populations, increase in TAp63 levels was accompanied by overexpression of DeltaNp73. This observation suggests complex regulatory cross talks between the different isoforms of the p53 family. In conclusion, p63 exhibits several transcriptional and stress-response properties similar to those of p53, suggesting that p63 activities should be taken into consideration in approaches to improve cancer therapies based on genotoxic agents.
  Carcinogenesis 03/2008; 29(2):273-81. · 5.70 Impact Factor
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  Available from: PubMed Central

  Article: Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype.

  B P Bouchet, J Bertholon, N Falette, C Audoynaud, C Lamblot, A Puisieux, C M Galmarini
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  ABSTRACT: Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n=20), and sensitive controls (control clones, CCs; n=10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and post-translational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis.
  British Journal of Cancer 12/2007; 97(9):1218-24. · 5.04 Impact Factor
• Article: TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts.

  M Brunori, N Mathieu, M Ricoul, S Bauwens, C E Koering, A Roborel de Climens, A Belleville, Q Wang, I Puisieux, D Décimo, A Puisieux, L Sabatier, E Gilson
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  ABSTRACT: Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to gamma-radiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.
  Oncogene 03/2006; 25(7):990-7. · 6.37 Impact Factor
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  Available from: PubMed Central

  Article: A twist for survival and cancer progression.

  A Puisieux, S Valsesia-Wittmann, S Ansieau
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  ABSTRACT: A major obstacle to the expansion of abnormal cells with significant proliferative potential is the induction of programmed cell death. Consequently, oncogene-driven hyperproliferation must be associated with apoptosis inhibition to allow malignant outgrowth. The oncogenic cooperation of N-Myc and Twist-1 in the development of neuroblastoma, the most common and deadly solid tumour of childhood, perfectly illustrates such a process. N-Myc promotes cell proliferation, whereas Twist-1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway. On the basis of numerous recent studies reporting its overexpression in a variety of human cancers, we discuss in this review the role of Twist-1 as a potent inhibitor of the cell safety programs engaged in response to an abnormal mitogenic activity.
  British Journal of Cancer 02/2006; 94(1):13-7. · 5.04 Impact Factor
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  Available from: PubMed Central

  Article: Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics.

  C M Galmarini, K Kamath, A Vanier-Viornery, V Hervieu, E Peiller, N Falette, A Puisieux, M Ann Jordan, C Dumontet
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  ABSTRACT: In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.
  British Journal of Cancer 07/2003; 88(11):1793-9. · 5.04 Impact Factor
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  Available from: nih.gov

  Article: Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity.

  C M Galmarini, N Falette, E Tabone, C Levrat, R Britten, N Voorzanger-Rousselot, O Roesch-Gateau, A Vanier-Viornery, A Puisieux, C Dumontet
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  ABSTRACT: The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G(2)/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G(1)cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade.
  British Journal of Cancer 10/2001; 85(6):902-8. · 5.04 Impact Factor
• Article: p53 induction prevents accumulation of aberrant transcripts in cancer cells.

  C Moyret-Lalle, C Duriez, J Van Kerckhove, C Gilbert, Q Wang, A Puisieux
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  ABSTRACT: Loss of fidelity of the splicing process occurs during tumor progression and can have a deleterious effect on genes like tumor suppressor genes. It was reported recently that the presence of aberrant transcripts of the TSG101 gene in breast cancer cells was associated with the mutation of the p53 tumor suppressor gene. On the basis of this observation, we have analyzed TSG101 transcript patterns in p53-active and p53-inactive cells. Using several isogenic cellular models, we demonstrate that the induction of p53 in cancer cells leads to a significant decrease of aberrant transcripts levels. This indicates a novel implication of p53 in the regulation of the splicing process.
  Cancer Research 02/2001; 61(2):486-8. · 7.86 Impact Factor
• Article: Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments.

  F Charbonnier, G Raux, Q Wang, N Drouot, F Cordier, J M Limacher, J C Saurin, A Puisieux, S Olschwang, T Frebourg
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  ABSTRACT: Large genomic deletions within the mismatch repair MLH1 and MSH2 genes have been identified in families with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and their detection represents a technical problem. To facilitate their detection, we developed a simple semiquantitative procedure based on the multiplex PCR of short fluorescent fragments. This method allowed us to confirm in HNPCC families three known deletions of MLH1 or MSH2 and to detect in 19 HNPCC families, in which analysis of mismatch repair genes using classical methods had revealed no alteration, a deletion of exon 5 and a duplication of MSH2 involving exons 9 and 10. The presence of such duplications, the frequency of which is probably underestimated, must be considered in HNPCC families in which conventional screening methods have failed to detect mutations.
  Cancer Research 07/2000; 60(11):2760-3. · 7.86 Impact Factor
• Article: Absence of p53-dependent induction of the metastatic suppressor KAI1 gene after DNA damage.

  C Duriez, N Falette, U Cortes, C Moyret-Lalle, A Puisieux
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  ABSTRACT: The p53 tumor suppressor protein functions to monitor the integrity of the genome. If a damage is detected, p53 binds tightly to specific sequence elements in the DNA and induces the transactivation of genes involved in various growth regulatory processes such as cell cycle progression, DNA repair and apoptosis. A p53-binding site was recently identified in the promoter region of the metastatic suppressor KAI1 gene, suggesting that this gene was a direct transcriptional target of p53. To test the relevance of this hypothesis, we studied the endogenous KAI1 expression in a series of human cell lines with varying p53 status in response to genotoxic treatment as well as in different cellular models exhibiting an inducible p53 activity. Overall, our data indicate that KAI1 expression is not significantly modulated by p53. This observation provides a direct evidence that the presence of a p53-binding site in regulatory domains is not a sufficient criteria to define a p53-transcriptional target gene.
  Oncogene 06/2000; 19(20):2461-4. · 6.37 Impact Factor