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

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-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...

Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity

“…In head and neck squamous cancer cells, it is shown that gefitinib induces both p21 WAF1/CIP1 and p27 Kip1 , accompanied by G1 cell cycle arrest (35). In the present study, however, we found that cell cycle arrest by gefitinib in COLM-5 cells was mainly mediated by the upregulation of p27 , a main target of P53, was not expressed at all in COLM-5 cells, possibly due to the lack of induction by the mutated P53 (36). We found a significant increase in p27…”

p53 as an Effector or Inhibitor of Therapy Response

“…From a mechanistic point of view, these human studies were strongly backed by animal data, initially from xenograft and subsequently from genetically defined mouse models (Varna et al 2009;Jackson et al 2012). Collectively, they support a model wherein absence of p53-enforced G 2 /M checkpoint in p53-mutant tumor cells treated with chemotherapy allows crosslinked chromosomes to enter mitosis, precipitating mitotic catastrophe (Fig.…”

Cyclopentenyl Cytosine Induces Senescence in Breast Cancer Cells through the Nucleolar Stress Response and Activation of p53

“…Some anticancer agents induce a rapid, non-telomere-dependent form of senescence, often termed premature senescence, in cancer cells at concentrations that do not cause acute cell death in vitro or in vivo (Hornsby, 2007). These agents include phosphoinositide-3 kinase inhibitors (Collado et al, 2000), retinoic acid (Roninson and Dokmanovic, 2003), microtubule-stabilizing agents (Arthur et al, 2007), Sirt1 (Ota et al, 2006), and DNA topoisomerase inhibitors (Michishita et al, 1998), doxorubicin (Vigneron et al, 2005) and cisplatin (Varna et al, 2009). Induction of SA-␤-gal staining after chemotherapy has been observed in cells obtained from patients with breast cancer (te Poele et al, 2002), and senescence-like growth arrest has been proposed as a determinant of in vivo tumor response to both selective chemotherapeutic agents and ionizing radiation (Kahlem et al, 2004).…”