CONTACT

Muriel Le Romancer
Team leader

muriel.leromancer
@lyon.unicancer.fr

+33 4 78 78 28 22

Cheney D - 4th floor

Centre Léon Bérard
28 rue Laennec
69373 Lyon Cedex 08
France

CORBO Laura
Chef d'équipe
DR2 CNRS
laura.corbo@lyon.unicancer.fr
LE ROMANCER Muriel
COHEN Pascale
Professeur des universités UCBL1
pascale.cohen@univ-lyon1.fr
LINCET Hubert

Maitre de Conferences UCBL

TREILLIEUX Isabelle
Medecin Anatomo-Pathologie CLB

isabelle.treilleux@lyon.unicancer.fr

NASRI Farida
GRISARD Evelyne

Assistante Ingenieur
evelyne.grisard@univ-lyon1.fr

LANGUILAIRE Cecile
OMARJEE Soleilmane
BELLANGER Aurelie

Doctorante EDBMIC
anp.bellanger@gmail.com

LATTOUF Hanine

Doctorante Cotutelle Beirut/Lyon
hanine.lattouf@lyon.unicancer.fr

JACQUEMETTON Julien

Ingenieur d'Etudes INSERM
julien.jacquemetton@lyon.unicancer.fr

CHOUCAIR Ali
DONINI Caterina

Ingenieur de Recherche
caterina.donini@univ-lyon1.fr

RAMOUZ Raana

Ingenieur d'Etudes INSERM
rana.ramouz@lyon.unicancer.fr

MALBETEAU Lucie
EL HELOU Myriam

Doctorante Cotutelle

Voir les objectifs et projets Voir les publications

Collaborations

- Team labellisée "Ligue nationale contre le cancer" (LNCC) 
- Association pour la recherche sur le cancer (ARC) 
- Lyon Science Transfert
- Institut national du cancer (INCa) 

In addition, to develop these projects, the team develop many collaborations in France (Paris, Lyon, Montpellier, Illkrich, Marseille) but also abroad (Italie, Canada, Royaume-Uni, USA).

OBJECTIVES

Estrogen and its receptor ERa are major promoters of cell proliferation in both normal and neoplastic breast epithelium. 70% of breast tumours are estrogen–dependent and generally responsive to anti-hormonal therapy, although treatments are limited by the emergence of de novo and/or acquired resistance. Our project, based on the use of new cellular and mouse models and a large human breast tumour bank aims to underlie the role of estrogen signalling in normal breast development and to determine how these normal processes change with breast cancer initiation and progression. Our team is also interested in defining the molecular mechanisms of resistance to E2/ER targeted therapies to be able to predict resistance in the clinic and to develop strategies to prevent or to overcome it.

PROJECT

Estrogen plays an essential role in normal breast development and in breast cancer development and progression. The principal target of estrogen, the estrogen receptor (ER), a ligand-activated transcription factor, is found in 70% of breast tumors at diagnosis, together with a profile of ERa-regulated genes. ERa-positive tumors generally are responsive to anti-hormonal therapy, although a significant proportion of patients with this class of tumors does not respond to this therapy by the emergence of de novo and/or acquired resistance, which is a major clinical problem.

Our team has focused its efforts on dissecting the molecular mechanisms of estrogen signalling pathways and describing their physiopathological effects, with a special interest for breast carcinogenesis. We reported a novel paradigm of ERa regulation through its methylation by PRMT1 on arginine 260. This methylation event is required for mediating estrogen non genomic function, leading to the activation of multiple signal transduction cascades in the extranuclear compartment (i.e., nongenomic mechanism). Notably, we also demonstrated that this signalling pathway is deregulated in a subset of breast cancers.

Our model system to study the regulation of ERα-dependent transcription is based on the identification and characterization of a new transcriptional regulator of ERa, hCAF1. Recent results delineate a new regulatory role for this protein in STAT1-mediated interferon signalling.

Using DNA array screening, we have identified a new estrogen-regulated gene, ZNF217: a transcription factor with oncogenic properties. We have evidenced a deregulated expression of ZNF217 in endocrine-resistant breast cancer cells and its involvement in epithelial-mesenchymal transition (EMT).

We have extensively explored hormone-resistance to ER ligands (tamoxifen and fulvestrant) and to the new molecules used for hormone therapy, aromatase inhibitors (AI). By means of new cellular models of acquired resistance we have developed novel strategies to revert resistance to the different molecules used in hormonal therapies.

Our research program, based on the use of new cellular and mouse models and a large human breast tumour bank from the Centre for Biological Resources (CBR) of Léon Bérard Cancer Center, will be directed towards understanding molecular and cellular mechanisms regulating estrogen signalling and how the deregulation of these mechanisms contributes to the development and/or the progression of breast cancer as well as to hormone-therapy resistance. Global gene expression methods will be used to detect several unique genes deregulated in tumorous and resistant phenotypes. It is anticipated that this program by its scale of investigation involving cellular and molecular approaches, innovative animal models representing a useful preclinical tool for testing drug responses, will lead to the identification of novel prognosis markers and might deliver potential molecular targets for therapeutic use.

PUBLICATIONS

Vilquin P., Donini C., Villedieu M., Grisard E., Corbo L., Bachelot T., Vendrell J. and Cohen P.A. miR-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer. Breast Cancer Res. (In press) 

Chapat C, Corbo L. Novel roles of the CCR4-NOT complex. Wiley Interdiscip Rev RNA. Nov 2014

Katia Bouchekioua-Bouzaghou, Coralie Poulard, Juliette Rambaud, Emilie Lavergne, Nader Hussein,, Marc Billaud, Thomas Bachelot, Sylvie Chabaud, Sylvie Mader,Guila Dayan, Isabelle Treilleux ,Laura Corbo and Muriel Le Romancer. LKB1 when associated with methylated ERa is a marker of bad prognosis in breast cancer.  Int J Cancer, Sep 2014.

Nguyen NT, Vendrell JA, Poulard C, Gyorffy B, Goddard-Léon S, Bièche I, Corbo L, Treilleux I, Le Romancer M, Cohen PA. A functional interplay between ZNF217 and Estrogen receptor alpha exists in luminal breast cancers. Mol. Oncol. (2014)

Fabrice André , Thomas Bachelot, Frederic Commo, Mario Campone, Monica Arnedos, Véronique Dieras, Magali Lacroix-Triki, Ludovic Lacroix, Pascale Cohen, David Gentien, Jose Adélaide, Florence Dalenc, Anthony Goncalves, Christelle Levy, Jean-Marc Ferrero, Jacques Bonneterre, Claudia Lefeuvre, Marta Jimenez,Thomas Filleron, Hervé Bonnefoi. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial.Lancet Oncology 2014

Coralie Poulard, Juliette Rambaud, Nader Hussein, Laura Corbo and Muriel Le Romancer. JMJD6 regulates ERα methylation on arginine. Plos One, Feb 2014 

Poulard C, Rambaud J, Le Romancer M, Corbo L. Proximity ligation assay to detect and localize the interactions of ERα with PI3-K and Src in breast cancer cells and tumor samples. Methods Mol Biol. 2014 

Guen VJ, Gamble C, Flajolet M, Unger S, Thollet A, Ferandin Y, Superti-Furga A, Cohen PA, Meijer L, Colas. CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. P. Proc Natl Acad Sci U S A. 2013

Vilquin P., Villedieu M., Grisard E., Ben larbi S., Ghayad S., Heudel P., Bachelot T., Corbo L., Treilleux I., Vendrell J. and CohenPA. Molecular characterization of anastrozole resistance in breast cancer: pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK-2206 with an aromatase inhibitor. Int J of cancer. (2013)

E. Prestat, S. Rodrigues de Morais, J. Vendrell, A. Thollet, C. Gautier, P. Cohen and A. Aussem. Learning the local Bayesian network structure around the ZNF217 oncogene in breast tumours.Computers in Biology and Medicine (2013)

 Chapat C, Kolytcheff C, Le Romancer M, Auboeuf D, De La Grange P, Chettab K, Sentis S and Corbo L.hCAF1 regulates interferon signalling by targeting STAT1. (2013). The EMBO Journal. 2013 Feb 5. doi: 10.1038

Poulard C, Treilleux I, Lavergne E, Bouchekioua-Bouzaghou K, Goddard-Leon S, Chabaud S, Trédan O, Corbo L and Le Romancer M. "Activation of rapid oestrogen signalling in aggressive human breast cancers". EMBO Mol Med. 2012 Oct 15

Vendrell JA, Thollet A.,Nguyen NT, Ghayad SE., Vinot S., Biéche I., Grisard E., Josserand V., Coll JL., Roux P., Corbo L., Treilleux I., Rimokh R., and Cohen PA. "ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion". Cancer Research. 2012 Jul 15.

Romancer, M., Poulard, C., Sentis, S., and Corbo, L. (2012). Post-translational Modifications of ER Alpha in Rapid Estrogen Action in Advances in Rapid Sex-Steroid Action. G. Castoria and A. Migliaccio, eds. Springer New York, pp. 79-93. 

Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L. “Cracking the EstrogenReceptor's Posttranslational Code in Breast Tumors” Endocrine Reviews. (2011) 32(5):597-622. 
  
Thollet A, Vendrell JA, Payen L, Ghayad SE, Ben Larbi S, Grisard E, Collins C, Villedieu M, Cohen PA.ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells. Molecular Cancer. (2010) 9:291. 

Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I, Cohen PA. Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathway. Int. J. of Cancer (2010) 126, 546-562. 

Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V Protein arginine methylation in estrogen signaling and estrogen-related cancers. Trends Endocrinol Metab (2010) 21:181-189 

Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse Y, Sentis S, Bouchekioua-Bouzaghou K, Goddard S, Gobert-Gosse S and Corbo L. Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol Cell (2008) 31:212-221. 

Robin-Lespinasse Y, S Sentis, C Kolytcheff, M-C Rostan Corbo L and M Le Romancer hCAF1, a new regulator of PRMT1-dependent arginine méthylation, J. Cell Sci (2007) 15;120:638-47

Vendrell JA, Ghayad S, Ben-Larbi S, Dumontet C, Mechti N, Cohen PA. A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen-resistance in breast cancer cells. Oncogene (2007) 26, 4656-67.


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