p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors
p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors
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DOI：
10.1002/ijc.24049
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发表时间：
2009-02-15
影响因子：
6.4
通讯作者：
Bertheau, Philippe
中科院分区：
文献类型：
--
作者：
Varna, Mariana;Lehmann-Che, Jacqueline;Bertheau, Philippe
一线化疗治疗乳腺癌患者的主要长期预后因素是对治疗的反应。我们以前已经表明，只有在携带TP 53突变的人类肿瘤中观察到对高剂量表柔比星-环磷酰胺的完全反应。三个异种移植的人类乳腺肿瘤。研究了其中2例TP 53突变患者和1例无TP 53突变患者对该药物联合的即时反应。细胞周期。在处理之前和之后在组织切片上表征和定量细胞衰老和细胞死亡。TP 53野生型肿瘤表现出强烈的早期诱导衰老样表型，SA-β-gal和p21过表达（CIPI）。相反，两种TP 53突变的肿瘤均未显示细胞周期停滞或衰老的迹象。相反，异常有丝分裂强烈增加，只有在TP 53突变的肿瘤。因此，在这些体内模型中，表柔比星-环磷酰胺治疗诱导TP 53野生型肿瘤中的衰老样特征，可能是细胞周期停滞和随后对治疗的抗性的原因。相反，在TP 53突变的肿瘤中，化疗诱导有丝分裂灾难和肿瘤死亡，这只在TP 53突变的肿瘤患者中解释了对这种关联的完全反应。(C)2008年威利-利斯。Inc.
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 epirobicin-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-beta-gal and p21(CIPI). 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. (C) 2008 Wiley-Liss. Inc.