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Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells
- 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.
- Subjects :
- Cancer Research
Gene Dosage
Mice, SCID
Genome
Epigenesis, Genetic
Mice
0302 clinical medicine
oncogene
Gene expression
Oncogene Proteins
0303 health sciences
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
Cell biology
Gene Expression Regulation, Neoplastic
Cell Transformation, Neoplastic
Oncology
030220 oncology & carcinogenesis
DNA methylation
Heterografts
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Female
Cell type
Mice, Nude
Breast Neoplasms
[SDV.CAN]Life Sciences [q-bio]/Cancer
Wnt1 Protein
Biology
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
breast cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Cyclin E
Animals
Humans
Epigenetics
Mammary Glands, Human
genome
Gene
030304 developmental biology
Oncogene
Genome, Human
modifications
Epithelial Cells
cell type
Oncogenes
Epigenome
DNA Methylation
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- ISSN :
- 10970215 and 00207136
- Volume :
- 145
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....6d8967e09cf12d223f02dc7f66f8e436