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Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells

Authors :
Beatrice Orsetti
Ambre Bender
Claude Sardet
Anne Saumet
Stanislas du Manoir
Elouan Cleroux
Amanda Abi-Khalil
Emeline Schmitt
Jacques Colinge
Charles Theillet
Michael Weber
William Jacot
Claire Fonti
Michael Dumas
Theillet, Charles
Blanc - Altérations épigénétiques et génétiques associées aux étapes précoces de la transformation maligne : étude d'un système modèle sur cellules primaires hMEC - - ESCATMO2009 - ANR-09-BLAN-0261 - Blanc - VALID
Identification of novel functions and regulators of DNA methylation in mammals - TRANSMETH - - EC:FP7:ERC2014-06-01 - 2019-05-31 - 615371 - VALID
Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM)
CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Biotechnologie et signalisation cellulaire (BSC)
Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Agence Nationale pour la Recherche ANR projet blanc ESCATMO. Anne Saumet was supported by ESCATMO, MESR doctoral fellowship to Claire Fonti. SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553. European Research Council ERC Consolidator grant n°615371 to Michael Weber.
ANR-09-BLAN-0261,ESCATMO,Altérations épigénétiques et génétiques associées aux étapes précoces de la transformation maligne : étude d'un système modèle sur cellules primaires hMEC(2009)
European Project: 615371,EC:FP7:ERC,ERC-2013-CoG,TRANSMETH(2014)
Source :
International Journal of Cancer, International Journal of Cancer, 2019, 145 (5), pp.1299-1311. ⟨10.1002/ijc.32413⟩, International Journal of Cancer, Wiley, 2019, 145 (5), pp.1299-1311. ⟨10.1002/ijc.32413⟩
Publication Year :
2019
Publisher :
Wiley, 2019.

Abstract

Claire Fonti and Anne Saumet contributed equally to this work.; International audience; Molecular subtypes of breast cancer are defined on the basis of gene expression and genomic/epigenetic pattern differences. Different subtypes are thought to originate from distinct cell lineages, but the early activation of an oncogene could also play a role. It is difficult to discriminate the respective inputs of oncogene activation or cell type of origin. In this work, we wished to determine whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. To this aim, we transduced shp53 immortalized HMECs in parallel with the CCNE1, WNT1 and RASv12 oncogenes which activate distinct oncogenic pathways and characterized them at sequential stages of transformation for changes in their genetic and epigenetic profiles. We show that initial activation of CCNE1, WNT1 and RASv12, in shp53 HMECs results in different and reproducible changes in mRNA and micro-RNA expression, copy number alterations (CNA) and DNA methylation profiles. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs. Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.

Details

ISSN :
10970215 and 00207136
Volume :
145
Database :
OpenAIRE
Journal :
International Journal of Cancer
Accession number :
edsair.doi.dedup.....6d8967e09cf12d223f02dc7f66f8e436