Author(s) : Sandra Angèle, Philippe Tanière, Janet Hall, Groupe de réparation de l'ADN, Centre international de recherche sur le cancer, 150, Cours Albert-Thomas, 69372 Lyon Cedex 08.
Summary : The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.
Figure 1. Interaction de la
protéine ATM avec d'autres protéines impliquées dans
la tumorigenèse mammaire. En réponse aux lésions
de l'ADN, ATM phosphoryle (P) directement les protéines BRCA1 et
p53 transactivatrices de gènes impliqués dans l'homéostasie
cellulaire. ATM peut également phosphoryler d'autres protéines
comme Chk2, MDM2 ou CtIP qui peuvent, à leur tour, phosphoryler ou
interagir (<=>) avec p53 ou BRCA1. L'altération de la voie
de signalisation ATM/p53 dans les cancers du sein sporadiques pourrait donc
entraîner une instabilité génomique participant au développement
tumoral.
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