Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite knowledge of oestrogen receptor status, it is not always possible to predict which breast cancers will respond to tamoxifen. We have previously reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen receptor (ER)-positive breast cancer. In this study, we confirm that the expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and mitosis respectively, within these untreated breast cancers, with an inverse relationship between Bcl-2 expression and the apoptotic index (P<0.05), and a positive relationship between Ki-S1 expression and the mitotic index (P<0.01). However, after 3 months' tamoxifen treatment these relationships were no longer apparent. Moreover, amongst the 27 tumours in which Bcl-2 expression was reduced during the 3 months' therapy, there was a significant correlation between the response to therapy and the increase in apoptosis (P<0.05), whereas in those tumours in which Bcl-2 did not fall with therapy, there was a significant correlation between response and the decrease in mitosis (P<0.05). These data suggest there are at least two mechanisms for effective tamoxifen therapy: increased apoptosis as a consequence of reduced Bcl-2 expression, and decreased proliferation.
 ...
PMID:Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes. 1078 88

Little data are available concerning the molecular mechanisms of action of Brca1 and Brca2 in breast oncogenesis. Recent experimental results suggest that Brca1 plays a role in the regulation of apoptosis. In order to determine whether the analysis of human tumours would provide data supporting this hypothesis, we have assessed the expression of the antiapoptotic bcl-2 and of the proapoptotic p53 genes in Brca1 - and Brca2 -associated breast carcinomas. The levels of expression of these genes were compared to those observed in controls and to the mitotic and the apoptotic indexes. Our series were composed of 16 cases of breast carcinoma in women with a germline Brca1 gene mutation, and of four cases with Brca2 mutation. A group of 39 patients aged under 36 years and for whom the search for Brca1 gene mutations was negative, and a group of 36 cases of sporadic cancers without data on their Brca status were used as controls. Immunohistochemistry was used to detect p53 and bcl-2 gene products. Mitotic and apoptotic indexes were higher in Brca1 -associated tumours than in controls. No significant difference in p53 immunostaining was observed between the four groups of patients. In contrast, the rate of bcl-2 -positive tumours was lower (31%) in Brca1 -carcinomas than in carcinomas without Brca1 mutation (90%) (P< 10(-3)). A strong Bcl-2 expression was found in the four cases of Brca2 -associated carcinomas. No significant correlation was observed between p53 and Bcl-2 immunostainings, either in cases or in controls. The association between Brca1 status and Bcl-2 expression remained significant after adjustment for the oestrogen receptor status. Our study shows that a low expression of bcl-2 characterises most Brca1 -associated breast carcinomas, a biological trait which seems not to be shared by Brca2 -associated tumours nor to be related to oestrogen receptor and/or p53 status. bcl-2 might thus be one of the target genes involved in the oncogenesis related to Brca1 and its down-regulation may account for the increased apoptosis and the high proliferative rate observed in Brca1 -associated carcinomas.
 ...
PMID:Low expression of bcl-2 in Brca1-associated breast cancers. 1104 56

The association between tumour shrinkage and reduction in kinetic cell activity after primary chemotherapy in human breast cancer is still a matter of investigation. 157 patients with T2-4, N0-1, M0 breast cancer received primary chemotherapy consisting of either the CMF regimen + tamoxifen (the first consecutive 76 cases) or the single agent epirubicin (the subsequent 81). Ki67, p53, bcl2, c-erbB2 and steroid hormone receptors were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery. Tumour shrinkage of >50% occurred in 72.4% of patients. Ki67 expression significantly decreased after chemotherapy; the reduction correlated with tumour response in both univariate (P < 0.005) and multivariate analysis (P = 0.02). p53, bcl-2, steroid hormone receptor and c-erbB2 immunostaining were scarcely affected. Baseline bcl2 (P = 0.04) and c-erbB2 (P = 0.02) were directly and inversely associated with the reduction in Ki67 immunostaining, respectively. Baseline p53 expression (P < 0.01) was directly related with Ki67 expression at residual tumour, whereas oestrogen receptor expression (P < 0.001) was inversely related. Ki67 at residual tumour was a better predictor for relapse-free survival (RFS) than baseline Ki67. Clinical response (P < 0.03), but not reduction in Ki67, was a significant independent predictor for disease recurrence. Chemotherapy was found to induce tumour shrinkage and to reduce the number of cells in the cell cycle, but its effect on tumour biology/aggressiveness was minimal. Reduction in Ki67 immunostaining correlated with clinical response but failed to be related to RFS. Ki67 expression at surgery rather than at baseline appears to be a better predictor for disease relapse.
 ...
PMID:Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. 1171 Aug 21

In oestrogen receptor (ER)-positive breast carcinoma cells, 17beta-oestradiol suppresses a dose-dependent induction of cell death by tumour necrosis factor alpha (TNF). The ability of oestrogens to promote cell survival in ER-positive breast carcinoma cells is linked to a coordinate increase in Bcl-2 expression, an effect that is blocked with the pure anti-oestrogen ICI 182,780. The role of Bcl-2 in MCF-7 cell survival was confirmed by stable overexpression of Bcl-2 which resulted in suppression of apoptosis induced by doxorubicin (DOX), paclitaxel (TAX) and TNF as compared to vector-control cells. The pure anti-oestrogen ICI 182,780 in combination with TNF, DOX or TAX potentiated apoptosis in vector-transfected cells. Interestingly, pre-treatment with ICI 182,780 markedly enhanced chemotherapeutic drug- or TNF-induced apoptosis in Bcl-2 expressing cells, an effect that was correlated with ICI 182,780 induced activation of c-Jun N-terminal kinase. Our results suggest that the effects of oestrogens/anti-oestrogens on the regulation of apoptosis may involve coordinate activation of signalling events and Bcl-2 expression.
 ...
PMID:Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens. 1173 51

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.
 ...
PMID:Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. 1187 May 34

Imbalance between pro-apoptotic and anti-apoptotic proteins, causing altered apoptosis, may lead to tumour development and tumour progression, and reduced response to adjuvant therapy. In this study, we evaluated the expression patterns of Bcl-2, Bcl-xL, and Bax protein in 126 primary invasive breast carcinomas, and the association with other clinicopathological parameters. We used immunohistochemical methods to evaluate protein expression. Reduced expression of both Bax and Bcl-2 was associated with lymphnode metastases in univariate analyses (one-way ANOVA) as well as in multivariate analysis (binary logistic regression) (Bcl-2 p=0.003 univariate, p=0.01 multivariate, Bax p=0.05 univariate, p=0.03 multivariate). Bcl-2 overexpression showed an inverse association with cyclin A (p=0.05), while expression of Bcl-xL showed an association only with cyclin D3 (p=0.04). Bcl-xL expression also showed a highly significant association with oestrogen receptor status (p=0.009). Bcl-2 and Bcl-xL showed an association with different D-type cyclins, indicating different pathways of pathogenesis. Expression of Bcl-2 was associated with better patient survival in univariate analysis (Kaplan meyer p=0.04), but lost its prognostic value in multivariate analysis (Cox regression p=0.2).
 ...
PMID:Reduced expression of both Bax and Bcl-2 is independently associated with lymph node metastasis in human breast carcinomas. 1207 74

The most appropriate systemic therapy for a population of patients with breast cancer is determined from clinical trial data. However, the heterogeneity of breast cancer is such that within a population individual patients derive variable benefit. There is therefore a need for predictive molecular factors in order that treatment can be individualised. This review describes the roles of HER-2, epidermal growth factor receptor (EGFR), oestrogen receptor (ER)/progesterone receptor (PgR), Ki67, Bcl-2, p53 and gene expression profiling in predicting responses to endocrine, cytotoxic and biological therapies. ER and PgR remain the only well-established predictive markers of responses to endocrine therapy, although HER-2/neu has an emerging role in this area and in choice of adjuvant chemotherapy. There are considerable methodological difficulties in identifying useful predictive factors but on the basis of current evidence other biomarkers add little additional information. The development of targeted therapies means that the molecular targets themselves may become useful predictive factors for directing use of these therapies. HER-2 already has an established role in this area, but the role of EGFR requires further elaboration. The use of DNA microarrays to assess gene expression profiles may revolutionise our ability to predict responses to therapy.
 ...
PMID:Predictors of response to systemic therapy in breast cancer. 1263 8

Morphological characteristics, grading features, proliferation marker MIB1, apoptosis (by Tdt-mediated duTP-biotin nick-end labelling (TUNEL)), Bcl-2 expression, oestrogen receptor (ER) and progesterone receptor (PgR) status were compared in ER-positive breast cancers before and after 3 months of neoadjuvant therapy with either letrozole or tamoxifen. Daily treatment was with letrozole 2.5 mg (12 patients) or 10 mg (12 patients), or with tamoxifen 20 mg(24 patients). Letrozole treatment was associated with a pathological response in 17 of 24 (71%) patients. The predominant change in grading features was a decrease in mitosis, and the expression of MIB1 was reduced in all of the 22 evaluable cases. Whilst only marginal changes were observed in ER expression following letrozole therapy, PgR reactivity was reduced in 20 of 21 evaluable cases which were initially PgR-positive, becoming undetectable in 16 patients. Tamoxifen treatment was associated with pathological response in 15 of 24 (63%) tumours. In contrast to letrozole, the dominant change in grading feature was an increase in tubule formation, ER score was markedly reduced in most cases, and the most common effect on PgR was an increased expression. Following treatment with either tamoxifen or letrozole, variable effects were observed on the apoptotic index and expression of Bcl-2. These results indicate that both letrozole and tamoxifen have marked influences on the pathological features of breast cancer during neoadjuvant therapy. However, the effects of the two agents varied such that the phenotypes of letrozole- and tamoxifen-treated tumours differ markedly. Effects on clinical, pathological and biological endpoints were frequently disconcordant--future studies will therefore require the evaluation of multiple parameters in order to fully assess tumour response.
 ...
PMID:Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen. 1275 76

A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10-28.5 microM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1-S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17beta-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.
 ...
PMID:Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells. 1471 Feb 35

Consumption of fruits and vegetables has been associated with cancer prevention; flavonoids are widely distributed in plant foods and considered to be the active ingredients. Quercetin and kaempferol are two of the most commonly found dietary flavonols, and have been reported to prevent cancer. We have previously reported that the isoflavone genistein and the flavone baicalein exert differential actions on the oestrogen receptor (OR) alpha in HepG2 cells. Because of the structural resemblance to both isoflavone and flavone, we examined the effects of these dietary flavonols on ORalpha- and ORbeta-specific transactivations and their subsequent involvement in inducing MCF-7 cell death. In the present study, both quercetin and kaempferol were able to compete for OR binding in a cell-free system and were agonistic to ORalpha and -beta expressed in HepG2 cells, while some additive effect was observed in the oestrogen response element (ORE)-driven transcription when 17beta-oestradiol was co-administered. Since the bcl-2 promoter contained two ORE, and ORE-driven transcriptional activity and Bcl-2 mRNA expression were increased by treatment with 10 microm-quercetin or kaempferol, it is possible that quercetin and kaempferol might up-regulate Bcl-2 expression through OR transactivation in MCF-7 cells. Cell death ELISA assay performed on MCF-7 cells indicated that an increase of apoptosis occurred at 25 microm-, but not 10 microm-, quercetin or kaempferol. Indirectly the results suggest that OR activation is not sufficient to induce apoptosis and that apoptosis is induced despite an increase in Bcl-2 expression.
 ...
PMID:Effect of dietary flavonols on oestrogen receptor transactivation and cell death induction. 1518 86


<< Previous 1 2 3 4 Next >>