Human Molecular Genetics, 2002, Vol. 11, No. 23 2887-2894
© 2002 Oxford University Press
Initiation of the breakage–fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I
1Génomique Fonctionnelle et Biologie Systémique en Santé, FRE 2571, Centre National de la Recherche Scientifique (CNRS), 19 rue Guy Moquet, 94801 Villejuif, France, 2UMR 147, CNRS, Institut Curie, 26 rue d'Ulm, 75005 Paris, France, 3Molecular Engines Laboratories, 20 rue Bouvier, 75011 Paris, France, 4URA 1960, CNRS, Institut Pasteur, 36 rue du Docteur Roux, 75015 Paris, France, 5International Institute of Genetics and Biophysics, CNR, via G. Marconi 10, 80125 Naples, Italy and 6Laboratoire de Génomique des Cancers, UMR 1599 CNRS, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France
Received July 1, 2002; Accepted September 6, 2002
Gene amplification plays a critical role in tumor progression. Hence, understanding the factors triggering this process in human cancers is an important concern. Unfortunately, the structures formed at early stages are usually unavailable for study, hampering the identification of the initiating events in tumors. Here, we show that the region containing the PIP gene, which is overexpressed in 80% of primary and metastatic breast cancers, is duplicated in the breast carcinoma cell line T47D. The two copies are organized as a large palindrome, lying ‘in loco’ on one chromosome 7. Such features constitute the landmark of the breakage–fusion-bridge (BFB) cycle mechanism. In hamster cells selected in vitro to resist cytotoxic drugs, common fragile site (CFS) activation has been shown to trigger this mechanism. Here, we characterize FRA7I at the molecular level and demonstrate that it lies 2 Mb telomeric to the PIP gene and sets the distal end of the repeated sequence. Moreover, our results suggest that the BFB process was frozen within the first cycle by healing of the broken chromosome. T47D cells thus offer a unique opportunity to observe the earliest products of the BFB cycle mechanism. Our findings constitute the first evidence that this amplification mechanism can be initiated in vivo by fragile site activation.
* To whom correspondence should be addressed at: FRE 2571 CNRS, 19 rue Guy Moquet, BP 8, 94801 Villejuif, France. Tel: +33 149583496; Fax: +33 149583509, Email: piatier{at}vjf.cnrs.fr
The authors wish it to be known that, in their opinion, these two authors should be considered as joint Second Authors.
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