Virginie Maire
Curie Institute
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Featured researches published by Virginie Maire.
Breast Cancer Research | 2008
Bérengère Marty; Virginie Maire; Eléonore Gravier; Guillem Rigaill; Anne Vincent-Salomon; Marion Kappler; Ingrid Lebigot; Fathia Djelti; Audrey Tourdès; Pierre Gestraud; Philippe Hupé; Emmanuel Barillot; Francisco Cruzalegui; Gordon Tucker; Marc-Henri Stern; Jean Paul Thiery; John Hickman; Thierry Dubois
IntroductionBasal-like carcinomas (BLCs) and human epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers that have the most aggressive clinical behaviour. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we aimed to discover deregulated signalling pathways in human BLCs.MethodsIn this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in 13 BLCs, and compared it with a control series of 11 hormonal receptor negative- and grade III-matched HER2+ carcinomas. The two tumour populations were first characterised by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse-phase protein array technology and tissue microarray. The effects of the PI3K inhibition pathway on proliferation and apoptosis was further analysed in three human basal-like cell lines.ResultsThe PI3K pathway was found to be activated in BLCs and up-regulated compared with HER2+ tumours as shown by a significantly increased activation of the downstream targets Akt and mTOR (mammalian target of rapamycin). BLCs expressed significantly lower levels of the tumour suppressor PTEN and PTEN levels were significantly negatively correlated with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similar to human samples, basal-like cell lines exhibited an activation of PI3K/Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was specifically observed after PI3K inhibition.ConclusionsThese data provide insight into the molecular pathogenesis of BLCs and implicate the PTEN-dependent activated Akt signalling pathway as a potential therapeutic target for the management of patients with poor prognosis BLCs.
Cancer Research | 2013
Virginie Maire; Fariba Nemati; Marion Richardson; Anne Vincent-Salomon; Bruno Tesson; Guillem Rigaill; Eléonore Gravier; Bérengère Marty-Prouvost; Leanne De Koning; Guillaume Lang; David Gentien; Aurélie Dumont; Emmanuel Barillot; Elisabetta Marangoni; Didier Decaudin; Sergio Roman-Roman; Alain Pierré; Francisco Cruzalegui; Stéphane Depil; Gordon Tucker; Thierry Dubois
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC.
PLOS ONE | 2013
Virginie Maire; Céline Baldeyron; Marion Richardson; Bruno Tesson; Anne Vincent-Salomon; Eléonore Gravier; Bérengère Marty-Prouvost; Leanne De Koning; Guillem Rigaill; Aurélie Dumont; David Gentien; Emmanuel Barillot; Sergio Roman-Roman; Stéphane Depil; Francisco Cruzalegui; Alain Pierré; Gordon Tucker; Thierry Dubois
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
PLOS ONE | 2015
Sylvie Maubant; Bruno Tesson; Virginie Maire; Mengliang Ye; Guillem Rigaill; David Gentien; Francisco Cruzalegui; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
The canonical Wnt/β-catenin pathway is activated in triple-negative breast cancer (TNBC). The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change > 1.3) of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGFβ, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change >1.3) which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors.
Cancer Research | 2014
Sylvie Maubant; Virginie Maire; Bruno Tesson; Fariba Nemati; David Gentien; Bérengère Marty-Prouvost; Stéphane Depil; Francisco Cruzalegui; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
Treatment of patients with triple-negative breast cancers (TNBCs) remains a major challenge for oncologists and alternative treatments to conventional chemotherapies are needed to improve their survival. The Wnt/beta-catenin signaling, recently reported to be activated in TNBCs, may represent an interesting pathway to target. We report that both LRP5 and LRP6 Wnt coreceptors are more strongly expressed in TNBCs than in other breast tumor subtypes. As very few studies have explored potential differences between LRP5 and LRP6, we investigated the effects of modulating specifically LRP5 or LRP6 expression on Wnt signaling, cell viability and tumorigenesis in HCC38 and MDA-MB-468 TNBC cells. We found that these two cell lines are more similar to TNBC biopsy specimens in terms of Wnt pathway gene expression profiles than any other tested cell line. Unlike LRP5, LRP6 was involved in activating the canonical Wnt pathway in response to Wnt3a. LRP5 knockdown induced caspase-dependent apoptosis, whereas LRP6 knockdown had no such effect. Importantly, LRP5-depleted cells were more sensitive to conventional chemotherapy than cells depleted of LRP6. The knockdown of LRP5 or LRP6 decreased tumorigenesis both in vitro and in vivo. Overall, these data suggest that the LRP5 and LRP6 coreceptors have different functions in TNBCs, with LRP5 playing a preponderant role in survival control. Our data suggest that both LRP5 and LRP6 are potential treatment targets in TNBCs, but that LRP5 may be the most useful target, given the impact of its depletion on cell survival as well as on the response to anti-cancer drugs. Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Nemati, David Gentien, Berengere Marty-Prouvost, Stephane Depil, Francisco Cruzalegui, Gordon Tucker, Sergio Roman-Roman, Thierry Dubois. The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2764. doi:10.1158/1538-7445.AM2014-2764
Molecular Cancer Therapeutics | 2013
Sylvie Maubant; Virginie Maire; Bruno Tesson; Fariba Nemati; Aurélie Dumont; David Gentien; Bérengère Marty-Prouvost; Guillem Rigaill; Leanne De Koning; Anne Vincent-Salomon; Emmanuel Barillot; Didier Decaudin; Alain Pierré; Stéphane Depil; Francisco Cruzalegui; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
Introduction. Treatment of patients with triple-negative breast cancers (TNBCs) remains a major challenge for oncologists. Although they respond well to the current therapeutic strategies based on conventional chemotherapies, they represent a large proportion of breast cancer death due to a high recurrence rate. Alternative treatments are needed to improve survival of these patients. The Wnt/beta-catenin signaling, recently reported to be activated in TNBCs, may represent an interesting pathway to target. Methods. We analyzed mRNA, DNA and protein levels for the LRP5 and LRP6 Wnt coreceptors in our cohort of breast tumor biopsy specimens. We then identified which TNBC cell lines display the most similarity to TNBC tumors regarding the Wnt pathway status using a centroid approach. We investigated the effects of modulating LRP5 or LRP6 expression on Wnt signaling, cell viability and apoptosis. We evaluated the potential therapeutic value of targeting LRP5 and LRP6 in TNBCs, by performing depletion experiments and treating cells with a mixture of doxorubicin/cyclophosphamide. We also examined whether the depletion of LRP5 or LRP6 had an impact on tumorigenicicy in vitro, in soft-agar assays, and in vivo, in xenograft models. Results. Gene expression analyses revealed that both LRP5 and LRP6 Wnt coreceptors were more strongly expressed in TNBCs than in other breast tumor subtypes. HCC38 and MDA-MB-468 TNBC cells were more similar to TNBC biopsy specimens in terms of Wnt pathway gene expression profiles than any other tested cell line. Unlike LRP5, LRP6 was involved in activating the canonical Wnt pathway in response to Wnt3a. LRP5 knockdown induced caspase-dependent apoptosis, whereas LRP6 knockdown had no such effect. LRP5-depleted cells were also more sensitive to conventional chemotherapy than cells depleted of LRP6. The knockdown of LRP5 or LRP6 decreased tumorigenesis both in vitro and in vivo. Conclusions. These data indicate that the LRP5 and LRP6 have different functions in TNBCs, with LRP5 playing a preponderant role in survival control. Our data suggest that both coreceptors are potential treatment targets in TNBCs, but that LRP5 may be the most useful target, given the impact of its depletion on cell survival and the response to anti-cancer drugs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B233. Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Nemati, Aurelie Dumont, David Gentien, Berengere Marty-Prouvost, Guillem Rigaill, Leanne De Koning, Anne Vincent-Salomon, Emmanuel Barillot, Didier Decaudin, Alain Pierre, Stephane Depil, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B233.
Oncotarget | 2018
Sylvie Maubant; Tania Tahtouh; Amélie Brisson; Virginie Maire; Fariba Nemati; Bruno Tesson; Mengliang Ye; Guillem Rigaill; Maïté Noizet; Aurélie Dumont; David Gentien; Bérengère Marty-Prouvost; Leanne De Koning; Sardar Faisal Mahmood; Didier Decaudin; Francisco Cruzalegui; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo, identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo. These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC.
Cancer Research | 2016
David C. Silvestre; Amélie Brisson; Bérengère Marty-Prouvost; Mengliang Ye; Hélène Bonsang; Virginie Maire; Damarys Loew; David Gentien; Didier Meseure; Fabien Reyal; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 is overexpressed in all breast cancer subtypes compared to normal breast tissues. The depletion of PRMT1 using siRNA in breast cancer cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with a PRMT1 inhibitor blocked proliferation specifically in breast cancer cells, with no effect in normal breast cells. Importantly, the expression of PRMT1 is an indicator of prognosis and response to treatment specifically in TNBC patients. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. We show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Altogether, our results point out PRMT1 as an emerging target for the treatment of breast cancers. Citation Format: David Silvestre, Amelie Brisson, Berengere Marty-Prouvost, Mengliang Ye, Helene Bonsang, Virginie Maire, Damarys Loew, David Gentien, Didier Meseure, Fabien Reyal, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. Protein arginine methyltransferase 1 (PRMT1) is a candidate therapeutic target for breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3809.
Molecular Cancer Therapeutics | 2015
David C. Silvestre; Amélie Brisson; Bérengère Marty-Prouvost; David Gentien; Damarys Loew; Florent Dingli; Virginie Maire; Fariba Nemati; Mengliang Ye; Didier Meseure; André Nicolas; Sergio Roman-Roman; Thierry Dubois
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 was overexpressed in all breast cancer subtypes compared to normal breast tissue. The depletion of PRMT1 using siRNA in BC cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with Furamidine, a new PRMT1-specific inhibitor, blocked proliferation specifically in BC cells, with no measurable effect in normal breast cells. Furamidine treatment of a TNBC patient-derived xenograft (PDX) model significantly slowed tumor growth. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. Our results show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Our results point out PRMT1 as an emerging target for the treatment of BC. Citation Format: David C. Silvestre, Amelie Brisson, Berengere Marty-Prouvost, David Gentien, Damarys Loew, Florent Dingli, Virginie Maire, Fariba Nemati, Mengliang Ye, Didier Meseure, Andre Nicolas, Sergio Roman-Roman, Thierry Dubois. Identification and validation of PRMT1 as a therapeutic target in breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B164.
Cancer Research | 2015
Sylvie Maubant; Bruno Tesson; Virginie Maire; Mengliang Ye; Guillem Rigaill; David Gentien; Francisco Cruzalegui; Gordon Tucker; Sergio Roman-Roman; Thierry Dubois
The canonical Wnt/beta-catenin pathway has been shown to be activated in triple-negative breast cancer (TNBC). The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change > 1.3) of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGF-beta, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change >1.3) which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors. Citation Format: Sylvie Maubant, Bruno Tesson, Virginie Maire, Mengliang Ye, Guillem Rigaill, David Gentien, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. The Wnt3a targetome in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2015-41