(...) The main aim of this project is to determine whether aneuploidy is the cause or the consequence of chromosomal instability. To this end, a cell model in which telomeric length shortens below a critical length due to the permissivity of specific cell cycle checkpoints will be used to investigate the possible relationship between telomere shortening and aneuploidy formation. Mammary epithelial cells, from which most breast cancers derive, do not express telomerase activity and spontaneously loss p16 when they are grown in vitro or in the normal mammary gland. It has been shown that progressive telomere shortening in human mammary epithelial cells (HMEC) results in chromosomes with fused chromatids (SCF) as well as dicentric chromosomes. The entrance of these chromosomal configurations in BFB cycles drives massive structural chromosome instability. It has recently been observed that the cellular and molecular evolution of HMEC in vitro is remarkably similar to those occurring in normal HMEC during progression to a premalignant and malignat phenotype in vivo. Therefore, the in vitro cell system of HMEC can be highly useful in determining the initial pathways of carcinogenesis in human breast cancer as well as to determine whether aneuploidy or telomere dysfunction is responsible for the onset of chromosomal instability.
|Effective start/end date||1/10/06 → 30/09/09|
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