Impaired BAX protein expression in breast cancer: Mutational analysis of the BAX and thep53 gene

Sturm, Isrid; Papadopoulos, Sarantos; Hillebrand, Timo; Benter, T.; Lück, Hans-Joachim; Wolff, Gerhard; Dörken, Bernd; Daniel, Peter T.

doi:10.1002/1097-0215(20000815)87:4<517::aid-ijc9>3.0.co;2-b

Cited by 52 publications

(35 citation statements)

References 22 publications

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“…33 In contrast, the inactivation of p53 by mutation does not necessarily result in a loss of BAX expression because additional factors seem to be involved in the regulation of BAX gene expression. 32 In line with our earlier observations in colorectal carcinoma, 13 esophageal squamous cell carcinoma 17 and breast carcinoma, 32 we did not observe a significant difference in BAX expression between the p53 wildtype and the p53 mutant tumors. The mutational status of p53 is reflected by the expression of p21 Cip/WAF-1 that is impaired in colorectal carcinomas with a mutant p53 indicating the dominant role of p53 in regulating p21 expression.…”

Section: Discussionsupporting

confidence: 91%

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Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

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Sturm

Grabowski

et al. 2002

Intl Journal of Cancer

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Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p ‫؍‬ 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/ BAX pathway (i.e., BAX low/p53 mutated; p ‫؍‬ 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.

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Section: Discussionsupporting

confidence: 91%

“…The denatured fragments were analyzed on a 10% non-denaturing polyacrylamide gel at 500 V and 50 mA for 2 hr at 22°C in a Multiphor electrophoresis chamber (Pharmacia, Freiburg) and were subsequently visualized by silver staining as described. 32 …”

Section: Mutation Analysis For P53mentioning

confidence: 99%

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Schelwies

Sturm

Grabowski

et al. 2002

Intl Journal of Cancer

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“…Thus, caspase-3 could serve as a target gene to enhance chemosensitivity not only by gene transfer but also by new drugs even in situations where the activation of the mitochondrial apoptosome is defective, e.g. as consequence of a loss of Bax or overexpression of Bcl-2 which are both frequently observed in breast cancer and other tumors (Bargou et al, 1995;Sturm et al, 1999Sturm et al, , 2000Prokop et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

et al. 2001

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“…14,15,24 Murine monoclonal antibodies against Bax (clone YTH-2D2, Trevigen Inc., MD, USA, dilution 1 : 750) or p53 (clone DO-7, Dako, Denmark, dilution 1 : 75) were employed. A blinded approach was used for slide analysis.…”

Section: Immunohistochemistry For Bax and P53mentioning

confidence: 99%

“…14,23 Loss of Bax expression occurs, however, in consequence of disturbed transcriptional regulation in the vast majority of cancers. 5,7,14,15,17,24 Thus, no concise data were so far available regarding the consequences of p53 and Bax inactivation by mutation on disease prognosis in gastric and other gastrointestinal tumors. In this study, we therefore examined the inactivation of the p53 and Bax gene in a group of 116 patients with R0-resected, sporadic gastric cancer to determine the influence of these regulators on tumor biology and disease prognosis.…”

Section: Introductionmentioning

confidence: 99%

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

et al. 2003

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Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.

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Impaired BAX protein expression in breast cancer: Mutational analysis of the BAX and thep53 gene

Cited by 52 publications

References 22 publications

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

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