p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors

Authors

  • Mariana Varna,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Jacqueline Lehmann-Che,

    1. CNRS UMR 7151, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Biochemistry, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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  • Elisabeth Turpin,

    1. CNRS UMR 7151, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Biochemistry, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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  • Elizabetha Marangoni,

    1. Curie Institute, INSERM Transfert Department, Paris, France
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  • Morad El-Bouchtaoui,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Marion Jeanne,

    1. CNRS UMR 7151, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Carmen Grigoriu,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Pathology, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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  • Philippe Ratajczak,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Christophe Leboeuf,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Louis-François Plassa,

    1. Department of Biochemistry, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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  • Irmine Ferreira,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
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  • Marie-France Poupon,

    1. Curie Institute, INSERM Transfert Department, Paris, France
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  • Anne Janin,

    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Pathology, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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  • Hugues de Thé,

    1. CNRS UMR 7151, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Biochemistry, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
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    • Hugues de Thé and Philippe Bertheau contributed equally to this work.

  • Philippe Bertheau

    Corresponding author
    1. INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France
    2. Department of Pathology, Hospital Saint-Louis APHP Assistance Publique Hôpitaux de Paris, 1 av. C. Vellefaux, 75010, Paris, France
    • Service de Pathologie, Hôpital St-Louis, 1 av. C. Vellefaux 75010 Paris, France
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    • Hugues de Thé and Philippe Bertheau contributed equally to this work.

    • Fax: +33142494516.


Abstract

The major long-term prognostic factor for breast cancer patients treated by first-line chemotherapy is response to treatment. We have previously shown that complete responses to high doses epirubicin-cyclophosphamide were observed only in human tumors bearing a TP53 mutation. Three xenografted human breast tumors, 2 of them with a TP53 mutation and one of them without, were studied for their immediate response to this drug association. Cell cycle, cellular senescence and cell death were characterized and quantified on tissue section before and after treatment. The TP53 wild-type tumor showed a strong early induction of senescence-like phenotype with overexpression of SA-β-gal and p21CIP1. In contrast both TP53 mutated tumors showed no sign of cell cycle arrest or senescence. Conversely, abnormal mitoses strongly increased, only in TP53 mutated tumors. Thus, in these in vivo models, epirubicin-cyclophosphamide treatment induces senescence-like features in TP53 wild-type tumor, likely accounting for cell cycle arrest and subsequent resistance to treatment. Conversely in TP53 mutated tumors, chemotherapy induces mitotic catastrophe and tumor death, accounting for complete response to this association exclusively in patients with TP53 mutated tumors. © 2008 Wiley-Liss, Inc.

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