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Centrosome Amplification: A Potential Marker of Breast Cancer Agressiveness

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Annual summary 1 Jul 2003-30 Jun 2006

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The aim of our research is focused in elucidating the mechanisms by which the normal regulatory pathways coordinating centrosome duplication with cell cycle events may become uncoupled promoting breast cancer development, progression, chemoresistance and consequent poor outcome. The preliminary results reported in this grant suggest that the development and progression of breast cancer is a complex process involving the role of estrogens, growth factor signaling pathways and abrogation of the p53 protein leading to an inactivation of cell cycle checkpoints. We have demonstrated that although MCF-7 cells stable transfected with a dominant-negative p53 construct, maintain estrogen-dependent properties, the timing of centrosome duplication and cyclincdk complexes is deregulated following mitogen stimulation. Interestingly, over-expression of cyclin A plays a critical role in the development of centrosome amplification following hormone stimulation. We also have shown that genotoxic stress leads to centrosome amplification in MCF-7 breast cancer cells with mutant p53, but not in MCF-7 cells over-expressing oncoproteins in the EGF mitogen signaling pathway with wild-type p53 background. Our findings demonstrate that over-expression of EGF mitogen signaling proteins is not sufficient to induce centrosome amplification following genotoxic stress, conferring to p53 a key role in the control of centrosome homeostasis and genomic stability. They also suggest that chemotherapy agents inducing DNA damage may lead to the selection of resistant clones through centrosome amplification only in cells with mutant p53 regardless over-expression of the EGF signaling pathway.

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  • Psychology
  • Anatomy and Physiology
  • Medicine and Medical Research

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