Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Détails

ID Serval
serval:BIB_088C20C1C345
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.
Périodique
Journal of Biological Chemistry
Auteur(s)
Mandriota S.J., Buser R., Lesne L., Stouder C., Favaudon V., Maechler P., Béna F., Clément V., Rüegg C., Montesano R., Sappino A.P.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Statut éditorial
Publié
Date de publication
2010
Volume
285
Numéro
17
Pages
13092-13106
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.
Mots-clé
Animals, Breast Neoplasms/genetics, Breast Neoplasms/metabolism, Cell Cycle Proteins/antagonists & inhibitors, Cell Cycle Proteins/genetics, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic/genetics, Cell Transformation, Neoplastic/metabolism, Cyclin-Dependent Kinase Inhibitor p21/genetics, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Cyclin-Dependent Kinase Inhibitor p27, DNA-Binding Proteins/antagonists & inhibitors, DNA-Binding Proteins/genetics, Down-Regulation/genetics, Epithelial Cells/metabolism, Epithelial Cells/pathology, Female, Gene Silencing, Genomic Instability, Humans, Intracellular Signaling Peptides and Proteins/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Mammary Glands, Human/metabolism, Mammary Glands, Human/pathology, Mice, Mice, Inbred NOD, Mice, SCID, Proteasome Endopeptidase Complex/genetics, Proteasome Endopeptidase Complex/metabolism, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Protein-Serine-Threonine Kinases/genetics, Tumor Suppressor Proteins/antagonists & inhibitors, Tumor Suppressor Proteins/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
01/03/2011 10:11
Dernière modification de la notice
20/08/2019 12:30
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