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-b-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. ' 2008 Wiley-Liss, Inc.Key words: epirubicin; cyclophosphamide; p53; senescence; breast; xenograft Chemotherapy has become an essential part of breast cancer treatment in the adjuvant or neoadjuvant settings. 1 Response to chemotherapy is one of the most important prognostic factors, especially when pathological complete response is achieved. 2,3 Apoptosis, 4 as well as senescence, 5-8 are major treatment-induced cellular events that can determine tumor sensitivity.p53 regulates cell fate in response to various stresses, either genotoxic or not genotoxic. 9 Among many possible effects, p53 can induce apoptosis, cell cycle arrest or senescence. Senescent cells are enlarged, flattened and granular, positive for SA-b-gal. 10 They often overexpress p53, p21 CIP1 and p16 The senescent state is characterized by an irreversible cellular growth arrest physiologically induced by telomere shortening (replicative senescence). In pathological conditions such as cellular stress, oncogene activation 15 or DNA damages, cells can develop a senescent phenotype, now recognized as ''accelerated'' senescence, [11][12][13][14][15][16] leading to complete growth arrest in only a few divisions, as compared to the 30-50 mitoses occurring before induction of replicative senescence. Accelerated senescence is believed to be a mechanism of protection against tumors. 17 It can be induced by DNA-damaging chemotherapy 18 and often requires functional p53. 19 We have previously shown that, in locally advanced breast cancer patients treated by high doses epirubicin/cyclophosphamide chemotherapy, pathologically assessed complete responses were observed only in TP53 mutated tumors, while all TP53 wild type tumors had incomplete response. 20,21 We hypothesized that breast tumor cells with wild-type TP...

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