The Bcl-2 Protein: a Prognostic Indicator Strongly Related to p53 Protein in Lymph Node-Negative Breast Cancer Patients

Silvestrini, Rosella; Veneroni, Silvia; Daidone, Maria Grazia; Benini, Elvira; Boracchi, Patrizia; Mezzetti, Maura; Fronzo, G. Di; Rilke, F; Veronesi, Umberto

doi:10.1093/jnci/86.7.499

Cited by 417 publications

(308 citation statements)

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“…In our study, contrary to what was observed in other tumour types (Silvestrini et al, 1994;Krajewski et al, 1995;Apolinario et al, 1997), no relationship was found between p53 and bax or bcl-2 protein expression, i.e., cases not expressing p53 did not present any clear upregulation of bax or downregulation of bcl-2. This finding could imply that bax or bcl-2 might be regulated by mechanisms other than p53, as already reported with regard to colorectal tumours (De Angelis et al, 1998) and other tumour types including breast cancer , non-small-cell lung cancer (Apolinario et al, 1997), squamous cell carcinoma of the larynx (Fracchiolla et al, 1999) and of the oral cavity (Costa et al, 1998).…”

Section: Discussioncontrasting

confidence: 99%

“…The last finding prompted us to investigate the information provided by bax, an apoptosis promoter, with that provided by bcl-2, an apoptosis suppressor. Previous reports on colorectal carcinoma established an association between bcl-2 positive staining and good prognosis (Ofner et al, 1995;Baretton et al, 1996), suggesting that bcl-2 promoted cell survival in slowly growing tumours, which was recently confirmed by Ogura et al (1999) and is in keeping with results obtained in other solid tumours (Silvestrini et al, 1994). All these studies, however, referred to patients with operable colorectal cancer submitted to surgery as the only therapeutic approach.…”

Section: Discussionmentioning

confidence: 66%

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Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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SummaryThe clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short-and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 66%

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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“…An important finding, with regard to the failure of Bcl-2 to predict responsiveness, seemed to be the strong negative correlation between Bcl-2 expression and p53 protein accumulation, in concordance with recent reports by other groups (Leek et al, 1994;Silvestrini et al, 1994;Joensuu et al, 1994;Gasparini et al, 1995). Recently, evidence has been obtained that wild-type as well as most mutant p53 proteins can down-regulate Bcl-2 expression in vitro and in vivo (Haldar et al, 1994;Selvakumaran et al, 1994;.…”

Section: Discussionsupporting

confidence: 87%

“…In this study, we assessed relationships between Bcl-2 expression and patient survival, response to adjuvant chemotherapy and a number of clinicopathological parameters in a series of 441 premenopausal, node-negative breast cancer patients. Bcl-2 has been reported to be frequently expressed in breast cancer and to be associated with favourable clinicopathological parameters and favourable prognosis in node-negative and node-positive breast cancers (Silvestrini et al, 1994;Joensuu et al, 1994). In women with node-positive breast cancer, Bcl-2 positivity was associated with favourable outcome in patients treated with adjuvant chemotherapy and/ or hormone therapy (Gasparini et al, 1995;Gee et al, 1994;Hellemans et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Slooten

Clahsen²,

Dierendonck³

et al. 1996

Br J Cancer

105

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Summary The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5+6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P<0.001) and progesterone receptor positivity (P<0.001) and low tumour grade (P<0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P<0.001) and c-erb-B-2 positivity (P<0.001), high Ki-67 index (P<0.001), mitotic index (P<0.001) and large tumour size (P=0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P=0.004) and overall (P=0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P=0.07) and negative (HR=0.55, 95% CI 0.27-1.12, P=0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.

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“…Paradoxically, high levels of Bcl-2 are also associated with delayed tumor progression, especially in breast cancer. Bcl-2 overexpression was found to Bcl-2 activates ATM in MCF-7 cells J Zhang et al associate with slower proliferation, high histological grade of differentiation, smaller tumor size and earlier stages of breast cancer development (Gee et al, 1994;Joensuu et al, 1994;Silvestrini et al, 1994;Daidone et al, 1999;Le et al, 1999). In several independent studies performed between 1995 and 2003, out of more than 1000 patients with stage I breast cancer who had been subjected to local-regional treatment, patients with Bcl-2-positive tumors were associated with lower relapse rates and increased overall survival during a 4-10 years of follow-up period (Silvestrini et al, 1994;Hellemans et al, 1995;Lipponen et al, 1995;Charpin et al, 1998;Daidone et al, 1999;Jager et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

et al. 2006

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Bcl-2 can both promote and attenuate tumorigenesis. Although the former function is relatively well characterized, the mechanism of the latter remains elusive. We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Consistent with p53 Ser15 being a target of ataxia telangiectasia mutated protein(ATM)/ATR (ATM-and rad3-related) in the DNA damage response, Bcl-2 activates ATM by inducing ATM Ser1981 phosphorylation, which is accompanied with the phosphorylaton of two additional ATM substrates, Chk2 Thr68 and H2AX Ser139. Downregulation of ATM using a specific small interference RNA fragment (ATMRNAi) abolished Bcl-2-induced p53pSer15 and Bcl-2-mediated growth inhibition of MCF7 cells. Ectopic expression of a dominant-negative p53 mutant, p53175H, partially rescued this growth inhibition. Taken together, these observations demonstrate the contribution of ATM-p53 function to Bcl-2-mediated inhibition of MCF7 cell growth, indicating an ATM-mediated surveillance system for regulating Bcl-2 overexpression. Consistent with this concept, we found that MCF7 cells express Bcl-2 heterogeneously with 34.5% of cells being Bcl-2 negative. In general, Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative. Thus, we provide evidence suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression.

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The Bcl-2 Protein: a Prognostic Indicator Strongly Related to p53 Protein in Lymph Node-Negative Breast Cancer Patients

Abstract: The predictive role of Bcl-2 expression on 6-year relapse-free and overall survival was mainly dependent on p53 expression.

Cited by 417 publications

References 0 publications

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

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