p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase

Fedier, André; Moawad, Ahmed W; Haller, U.; Fink, Daniel

doi:10.3892/ijo.23.5.1431

Cited by 10 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…They have reported statistically significant association between p53 immunopositivity and lack of response to adjuvant anthracycline based chemotherapy. Also in experimental studies performed on cell lines [19] or on mice with p53 lacking tumors [20] this effect was seen. These results can be explained in part by the fact that certain p53 gene can up-regulate the expression of multidrug resistance gene ( MDR1 ) via stimulation of gene promoter [34].…”

Section: Discussionmentioning

confidence: 95%

“…p53 contributes to angiogenesis regulation in two ways: it supports the secretion of inhibitory thrombospondin-1 and depresses the secretion of the vascular endothelial growth factor (VEGF) inducer [9]. Although experimental studies have clearly shown that p53 mutated form confers resistance to anthracyclines [19, 20], translational studies have demonstrated non-concordant data. Several reports [21–24] showed that p53 overexpression assessed by immunohistochemistry (IHC) correlated with resistance to anthracyclines, nevertheless other studies suggested lack of such relation [25–27].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

Biesaga¹,

Niemiec²,

Ziobro

2012

Pathol. Oncol. Res.

View full text Add to dashboard Cite

A considerable subgroup of patients with early breast cancer does not address benefits of anthracycline based chemotherapy. The aim of this retrospective study was to investigate the effect of microvessel density (MVD) and status of p53 protein on 5-year disease free survival (DFS) in the group of breast cancer patients treated with anthracyclines in adjuvant setting. Correlations between MVD, p53 status and other clinicopathological parameters were also assessed. MVD and p53 status were analyzed immunohistochemically in the group of 172 women with breast cancer in clinical stage T1-2, N1-N2, M0. There were 123 tumors (71.5 %) with lower MVD (≤214.8 microvesells/mm2) and 49 (28.5 %) with higher MVD (>214.8 microvesells/mm2). The proportion of higher MVD tumors significantly increased in N2 (P = 0.000) and in estrogen (P = 0.046) or progesterone receptors (P = 0.029) negative tumors. p53 positivity was indicated in 50 cancers (29.1 %) and was significantly associated with higher grade (P = 0.000), steroid receptors negativity (P = 0.000), cytokeratin5/6 positivity (P = 0.026), topoisomerase IIα overexpression (P = 0.005) and higher proliferation rate (P = 0.001). In univariate analysis, higher MVD (P = 0.016) and p53 negativity (P = 0.023) were significantly related with longer DFS (median follow-up 36 months). In multivariate Cox regression analysis MVD was independently associated with DFS. These data suggest that higher MVD is favourable prognostic factors for early advanced breast cancer patients after adjuvant anthracycline based chemotherapy.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

Biesaga¹,

Niemiec²,

Ziobro

2012

Pathol. Oncol. Res.

View full text Add to dashboard Cite

show abstract

“…Although in vitro studies have clearly shown that the mutated form of p53 confers resistance to anthracyclines, translational research studies in humans have generated large amounts of non-concordant data. When discussing about predictive value of p53 mutations, it is important to emphasize that (a) p53 mutations are associated with a basallike phenotype (11), a subclass highly sensitive to anthracyclines (16), (b) molecular pathways for cell death have been reported to be p53-dependant in BRCA1 wild type cell lines and p53-independent in BRCA1-mutated cell lines (27). From these two considerations emerges the hypothesis that p53 mutations could have a differential predictive value between basal-like tumors (BRCA1-mutated) and non-basal tumors.…”

Section: Limitations Of Research Based On a Single Predictive Biomarkmentioning

confidence: 99%

Heterogeneity of Breast Cancer among Patients and Implications for Patient Selection for Adjuvant Chemotherapy

Varga

2006

Pharm Res

View full text Add to dashboard Cite

Although the benefits of adjuvant chemotherapy are not controversial, the absolute effect of such therapy is small. Therefore, there is a need to identify biomarkers that can help select patients with localized breast cancer for treatment. Despite intense research in this field, no biomarker has been shown to be useful to predict benefit of adjuvant chemotherapy in daily practice. This can partially be explained by the fact that breast cancer is composed of several distinct subclasses, as shown by large-scale genomic analyses. In this review, we discuss why the current research approach based on a single biomarker is limited by the heterogeneity of cancer among patients. We then propose three solutions to improve the research strategies in this field: investigate one biomarker in a single homogeneous subclass to improve its predictive value; study the predictive value of multibiomarker assays in larger populations; and use functional pathways to predict the efficacy of a given drug.

show abstract

“…The increased chemosensitivity of ATMdeficient cells was not accompanied by increased apoptosis or further alteration of cell cycle checkpoint activation, suggesting that ATM may play a role in protective response to DNA damage independent of p53. In addition, the disruption of the DNA-PK gene in p53-deficient cells has been demonstrated to cause an increase in sensitivity to doxorubicin and epirubicin [Fedier et al, 2003a]. Doxorubicin-induced hypersensitivity in these cells correlated with transient G2/M checkpoint activation, suggesting that DNA-PK modulates p53-independent pathways in response to DNA damage induced by anthracyclines [Fedier et al, 2003a].…”

Section: Regulators Of P53mentioning

confidence: 99%

“…In addition, the disruption of the DNA-PK gene in p53-deficient cells has been demonstrated to cause an increase in sensitivity to doxorubicin and epirubicin [Fedier et al, 2003a]. Doxorubicin-induced hypersensitivity in these cells correlated with transient G2/M checkpoint activation, suggesting that DNA-PK modulates p53-independent pathways in response to DNA damage induced by anthracyclines [Fedier et al, 2003a]. Therefore, the inhibition of function of ATM, ATR, or DNA-PK in tumors may be a valuable approach to improve chemosensitivity in the treatment of cancers that carry mutant p53.…”

Section: Regulators Of P53mentioning

confidence: 99%

Pharmacogenomics of the p53 tumor suppressor and its role in cancer chemoresistance

Liu¹,

Bishop²,

Dasmahapatra³

et al. 2004

Drug Development Research

View full text Add to dashboard Cite

Drug resistance remains a key obstacle to successful cancer treatment. The implementation of pharmacogenomics is widely proclaimed as a route to revolutionize the face of cancer therapy. Here we discuss the pharmacogenomics of the p53 tumor suppressor and its role in cancer chemosensitivity. It has been proposed that p53 has a profound impact on the response to chemotherapy and participates in development of drug resistance in tumor cells. This is based on the dual role of p53 as a guardian of genome integrity and as a key mediator of apoptosis. Alterations of the p53 gene occur in approximately 50% of human cancer, and human tumor cells retaining wild-type p53 often have epigenetic defects in the p53 pathway. Extensive mechanistic studies of drug action suggest that virtually all cancer cells have a dysfunctional p53 system (including p53 and its associated proteins, both upstream regulators and downstream targets). Various experimental approaches to correct the p53 pathway defects in tumor cells are discussed. Many studies have correlated p53 status with prognosis and therapy response in tumors. However, the impact of p53 status on drug resistance of tumors is still controversial. The impact of p53 on chemosensitivity is complex and multifactorial, depending on the genotypic/phenotypic context of the cell. Recent technological achievements have fostered a renewed interest in pharmacogenomics of p53 and its association with drug response. These include high-throughput tissue microarray analysis of p53 protein expression, single nucleotide polymorphism genotyping of the p53 gene, and gene expression profiling to identify the gene signature of p53-associated chemoresistance. Knowledge from pharmacogenomic studies will provide an opportunity for improvements in drug efficacy through effective stratification of patients, and early identification of those individuals most likely to respond effectively to a specific therapy. Drug Dev.

show abstract

p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase

Cited by 10 publications

References 0 publications

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

Heterogeneity of Breast Cancer among Patients and Implications for Patient Selection for Adjuvant Chemotherapy

Pharmacogenomics of the p53 tumor suppressor and its role in cancer chemoresistance

Contact Info

Product

Resources

About