Varna Mariana, Lehmann-Che Jacqueline, Turpin Elisabeth, Marangoni Elizabetha, El-Bouchtaoui Morad, Jeanne Marion, Grigoriu Carmen, Ratajczak Philippe, Leboeuf Christophe, Plassa Louis-François, Ferreira Irmine, Poupon Marie-France, Janin Anne, de Thé Hugues, Bertheau Philippe
INSERM U728, University Institute of Hematology, University Paris 7 Denis Diderot, Paris, France.
Int J Cancer. 2009 Feb 15;124(4):991-7. doi: 10.1002/ijc.24049.
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-beta-gal and p21(CIP1). 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.
一线化疗治疗的乳腺癌患者的主要长期预后因素是对治疗的反应。我们之前已经表明，只有在携带TP53突变的人类肿瘤中才观察到对高剂量表柔比星-环磷酰胺的完全反应。研究了3种异种移植的人类乳腺肿瘤，其中2种携带TP53突变，1种不携带，观察它们对这种联合用药的即时反应。在治疗前后的组织切片上对细胞周期、细胞衰老和细胞死亡进行表征和定量。TP53野生型肿瘤表现出强烈的早期衰老样表型诱导，伴有SA-β-半乳糖苷酶和p21（CIP1）的过表达。相反，两种TP53突变肿瘤均未显示细胞周期停滞或衰老的迹象。相反，异常有丝分裂仅在TP53突变肿瘤中强烈增加。因此，在这些体内模型中，表柔比星-环磷酰胺治疗在TP53野生型肿瘤中诱导衰老样特征，这可能是细胞周期停滞和随后对治疗产生抗性的原因。相反，在TP53突变肿瘤中，化疗诱导有丝分裂灾难和肿瘤死亡，这解释了仅在TP53突变肿瘤患者中对这种联合用药的完全反应。
