Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

• Published in: The Journal of biological chemistry 2010-04, Vol.285 (17), p.13092-13106
• Main Authors: Mandriota, Stefano J., Buser, Raphaële, Lesne, Laurence, Stouder, Christelle, Favaudon, Vincent, Maechler, Pierre, Béna, Frédérique, Clément, Virginie, Rüegg, Curzio, Montesano, Roberto, Sappino, André-Pascal
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer/Breast; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cell/Cycle; Cell/Epithelial; Cellular Transformation; 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; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Dysplasia; 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; Molecular Bases of Disease; p21/Waf1/Cip1; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Transformation; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor/Suppressor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.078360

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 p21WAF1/CIP1 and p27KIP1 protein levels, whereas little or no effect was observed on p21WAF1/CIP1 or p27KIP1 mRNAs. p21WAF1/CIP1 silencing also increased MCF-10A cell proliferation, thus identifying p21WAF1/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.