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

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 res...

Full description

Saved in:
Bibliographic Details
Published in:International journal of cancer 2019-09, Vol.145 (5), p.1299-1311
Main Authors: Fonti, Claire, Saumet, Anne, Abi‐Khalil, Amanda, Orsetti, Béatrice, Cleroux, Elouan, Bender, Ambre, Dumas, Michael, Schmitt, Emeline, Colinge, Jacques, Jacot, William, Weber, Michael, Sardet, Claude, du Manoir, Stanislas, Theillet, Charles
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cell activation
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
cell type
Copy number
CpG islands
Cyclin E - biosynthesis
Cyclin E - genetics
Deoxyribonucleic acid
DNA
DNA Methylation
Epigenesis, Genetic
Epigenetics
Epithelial cells
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelial Cells - physiology
Female
Gene Dosage
Gene expression
Gene Expression Regulation, Neoplastic
Genetic transformation
genome
Genome, Human
Genomes
Genomics
Heterografts
Human health and pathology
Humans
Life Sciences
Mammary gland
Mammary Glands, Human - metabolism
Mammary Glands, Human - pathology
Mammary Glands, Human - physiology
Medical research
Mice
Mice, Nude
Mice, SCID
modifications
oncogene
Oncogene Proteins - biosynthesis
Oncogene Proteins - genetics
Oncogenes
Proto-Oncogene Proteins p21(ras) - biosynthesis
Proto-Oncogene Proteins p21(ras) - genetics
Wnt1 Protein - biosynthesis
Wnt1 Protein - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. What's new? Different molecular subtypes of breast cancer generally are assumed to arise from different cell lineages, though other activating factors may also be involved. Here, using engineered primary human mammary epithelial cell (HMEC) models, the authors show that founding oncogenic mutations that activate distinct cancer‐promoting pathways impact the molecular landscape of breast tumors. HMEC transformation induced by distinct oncogenes resulted in different, reproducible patterns of copy number aberrations and changes in DNA methylation. The findings indicate that phenotypic characteristics of tumors and their genomic and epigenetic profiles are strongly impacted by the early activation of oncogenic pathways.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.32413