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

Tumorigenesis is related to the dysregulation of cell growth or cell death pathways. Hence, elucidation of the mechanisms involved in the modulation of pro- or anti-apoptotic proteins is important in furthering understanding of breast cancer aetiology and may aid in designing prevention and treatment strategies. In the present study, we examined the role of 17beta-oestradiol on the regulation of apoptosis in the breast cancer cell line MCF-7. Using multi-probe RNAase protection assays, we found changes in the mRNA levels of several Bcl-2 family proteins upon treatment of MCF-7 cells with 17beta-oestradiol. Unexpectedly, we found a paradoxical effects of 17beta-oestradiol on two anti-apoptotic proteins Bcl-2 and Bcl-x. Treatment with 17beta-oestradiol resulted in up-regulation of Bcl-2 mRNA and protein, but down-regulated Bcl-x(L) mRNA and protein. The effect of 17beta-oestradiol on Bcl-x(L) occurred at concentration-dependent fashion. The effect was specific to 17beta-oestradiol since other steroid hormones exert no effect on Bcl-x(L). Tamoxifen, an anti-oestrogen, blocked the down-regulation of Bcl-x(L) by 17beta-oestradiol demonstrating this effect is oestrogen receptor-dependent. We speculate that different members of the Bcl-2 family proteins may be regulated through different pathway and these pathways may be modulated by 17beta-oestradiol.
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PMID:Paradoxical regulation of Bcl-2 family proteins by 17beta-oestradiol in human breast cancer cells MCF-7. 1050 61

Studies of the mechanism of actions of estrogen, antiestrogen and physical factors may provide clues to an understanding of breast cancer growth and/or regression regulation and thus identify novel targets for therapeutic intervention. Defective control of apoptosis appears to play a central role in the pathogenesis of neoplasia. Conversely, cancer therapy and ionizing radiation can induce cancer cell death by apoptosis and/or necrosis. bcl-2 gene and p-53 gene products have been both linked to programmed cell death pathways. We have analyzed the effect of estradiol, tamoxifen and UV exposure on the induction of apoptosis, expression of p53 and bcl-2 gene products as well as the proliferative activity (expressed as [3H]thymidine incorporation and PCNA and MPM2 antigens involvement) in MCF7. It has been found that estradiol increases the speed of cell cycle in MCF7 and acts as antiapoptotic factor. Tamoxifen has multiple influence on the rate of growth of cancer cells: depends on estrogen receptor (ER), conducts reduction of proliferation rate; depends on ER and other mechanisms conducts to suppressions of Bcl-2 protein expression and induction of cell death through apoptotic pathway. Estradiol prevents the apoptotic influence of tamoxifen probably by enhancement of Bcl-2 protein expression and does not prevent the inhibition of proliferation rate. The irradiation with UV induces apoptosis by over-expression of p53 and down-regulation of bcl-2 gene.
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PMID:Influence of estrogen, antiestrogen and UV-light on the balance between proliferation and apoptosis in MCF-7 breast adenocarcinoma cells culture. 1087 Jun 82

The survival benefit of adjuvant chemotherapy in node-positive patients with breast cancer compared with surgery alone has been established. The survival benefit differs considerably between hormone receptor-positive and -negative patients, and it is believed that the effectiveness of adjuvant chemotherapy can be increased by hormonal therapy with tamoxifen. In the present review, we discuss the rationale behind the effectiveness of combination treatment with anticancer drugs and tamoxifen in terms of the paradoxical role of Bcl-2 in apoptosis in breast cancer. The survival benefit between receptor-positive and -negative patients was assessed using previous reports of randomized controlled studies for postoperative adjuvant chemotherapy in node-positive breast cancer. Tamoxifen induces the anti-apoptotic gene, Bcl-2, by its effect on estradiol (E2), via an E2-response element in the promotor region of Bcl-2. The efficicacy of chemoendocrine therapy was assessed in terms of the influence of tamoxifen on the effect of anticancer drugs. Adjuvant chemotherapy, including anthracycline and non-anthracycline based regimens, has an overall survival benefit in node-positive breast cancer, with a 23.5% reduction in the annual odds of recurrence and a 15% reduction in mortality (P<0.00001). A comparison of the reduction of the relative risk indicates that the survival benefit in receptor-negative patients is superior to that in receptor-positive patients by approximately 3-fold. Further, in contrast to receptor-negative patients, there is no additional benefit from paclitaxel over doxorubicin and cyclophosphamide (AC) in receptor-positive patients. The possible reasons that the chemotherapy benefit in receptor-positive patients is small and marginal are the following: i) concurrent treatment or pretreatment with tamoxifen can increase plasma E2 levels in premenopausal patients, thereby inducing Bcl-2 in residual cancer cells, which might decrease drug-sensitivity in combination with chemotherapy; ii) induction of Bcl-2 might be involved predominantly in the resistance to taxanes, the cytotoxic action of which targets Bcl-2. Co-treatment or pretreatment with tamoxifen for adjuvant therapy might decrease the efficacy of anticancer drugs, an effect that is mediated by induction of Bcl-2, especially in premenopausal patients with node-positive breast cancer. Treatment with anticancer drugs should be followed by treatment with tamoxifen to produce a survival benefit from combination therapy in receptor-positive patients.
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PMID:A pitfall in the survival benefit of adjuvant chemotherapy for node- and hormone receptor-positive patients with breast cancer: the paradoxical role of Bcl-2 oncoprotein (review). 1160 12

Tamoxifen increases endometrial cell proliferation and the incidence of endometrial cancer in postmenopausal women. The purpose of this study was to evaluate apoptosis and apoptosis-related factors in endometrium in relation to tamoxifen exposure. We analyzed benign postmenopausal endometrium from breast cancer patients receiving tamoxifen (n = 35) and from controls (n = 24), and endometrial cancer tissue from tamoxifen-treated breast cancer patients (n = 15) and endometrial cancer from women without tamoxifen exposure (n = 51). Apoptosis was examined morphologically, and the percentage of apoptotic epithelial cells was defined as the apoptotic index. In the benign samples, the presence of apoptotic cells was also evaluated immunohistochemically by the expression of caspase-3 and the monoclonal antibody M30. The expression of Fas, FasL, and Bcl-2 was analyzed in all tissue samples. No differences were observed in the mean apoptotic index in benign endometrium in tamoxifen users (0.17%) versus controls (0.08%), or in tamoxifen-exposed (2.46%) versus nonexposed endometrial cancer (2.28%). However, the ratio of the apoptotic index with the previously reported proliferation index was lower in benign endometrium from tamoxifen users than in controls (0.02 +/- 0.026 vs. 0.05 +/- 0.03, Mann-Whitney U <0.005). In benign endometrium FasL was more frequently expressed in tamoxifen-users than in controls (chi(2) <0.05). We conclude that the apoptosis/proliferation ratio in benign endometrium from tamoxifen users is lower than in controls, indicating that the tamoxifen-induced higher proliferation is not compensated for by increased apoptosis. An imbalance between cell proliferation and apoptosis, and possibly suppression of the antitumor immune response by FasL overexpression in tamoxifen-exposed endometrium might play a role in the development of endometrial cancer in tamoxifen users.
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PMID:Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium. 1273 25

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.
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PMID:Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen. 1275 76

Tamoxifen causes apoptosis of malignant glial cells at a concentration that does not kill normal astrocytes. C6 glioma cells were stably transfected with a vector expressing Bcl-2 under the control of metallothionin promoter. Low leaky Bcl-2 expression offered complete protection against tamoxifen-induced apoptosis. High Bcl-2 levels, on the other hand, accelerated the apoptosis, with Bcl-2-overexpressing clones dying within 48 h of tamoxifen treatment as compared to 6 days for parental C6 cells. Overexpressed Bcl-2 is localized primarily in mitochondria and to a much lower extent in endoplasmic reticulum (ER). Only a minor fraction of the overexpressed Bcl-2 gets phosphorylated in tamoxifen-treated cells and the phosphorylation does not affect its binding to Bax. Tamoxifen treatment of Bcl-2-overexpressing clones was found to result in activation of c-Jun N-terminal kinase (JNK) and p38 kinase. Inhibition of JNK but not p38 kinase completely abrogated the accelerated apoptosis. Constitutively expressed endogenous c-Jun was found to be phosphorylated, resulting in increased activator protein 1 (AP-1) DNA-binding activity. Expression of Fas ligand (FasL), an AP-1 transcriptional target, increased during accelerated cell death. This presumably brought about activation of caspase 8, as inhibition of caspase 8 blocked the apoptosis. The JNK/c-Jun/AP-1/FasL pathway could be considered as a potential target for the therapy of gliomas.
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PMID:Activated JNK brings about accelerated apoptosis of Bcl-2-overexpressing C6 glioma cells on treatment with tamoxifen. 1560 91

Breast cancer is the most common cancer disease in women in the western world. Tamoxifen has been the standard first line endocrine therapy for patients with estrogen receptor (ER) positive tumors. Unfortunately, almost all patients with advanced disease develop tamoxifen resistance. This has lead to a search for new potent antiestrogens. One of the new compounds under development is the pure antiestrogen RU 58,668. To study the mechanisms behind acquired resistance to RU 58,668, the RU 58,668-resistant cell line MCF-7/RU58(R)-1 (RU58(R)-1) was developed. The RU58(R)-1 cell line was responsive to tamoxifen, but cross-resistant to ICI 182,780 and the estrogen-sensitivity was reduced compared to the parental MCF-7 cell line. The protein levels of ERalpha, IGF-I Receptor (IGF-IR) and Bcl-2 were severely reduced, when RU58(R)-1 cells were cultured with RU 58,668 and the expression of progesterone receptor (PR) was lost. The ERalpha level increased upon withdrawal of RU 58,668 and the ERalpha protein was destabilized by RU 58,668 in both cell lines. Regulation of most of the investigated estrogen-sensitive mRNAs was found to be normal in the resistant cells. The protein levels of IGF-IR, Bcl-2 and the IGF Binding Protein 2 (IGFBP2) reverted towards MCF-7 levels upon RU 58,668 withdrawal, but the resistant phenotype was maintained. Thus, it appears as acquired resistance to RU 58,668 is not a result of loss of the ERalpha expression or function and we suggest that in the presence of RU 58,668, the RU58(R)-1 cell line probably uses other mitogenic pathways than the ERalpha pathway for growth and survival.
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PMID:Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668. 1586 41

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.
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PMID:Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. 1621 79

Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-alpha (ER-alpha)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-alpha status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-alpha-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-alpha status.
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PMID:Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells. 1776 97

Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor-positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor-negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis-inducing effect of tamoxifen and evaluated the apoptosis-inducing pathway. The estrogen receptor-positive human leukemia cell line HL-60 and estrogen receptor-negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability-detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen-B had more potent cancer cell-damaging activity than tamoxifen. Ridaifen-B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen-B-induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen-B-induced apoptosis was estimated. Ridaifen-B significantly reduced mitochondrial membrane potential, and overexpression of Bcl-2 inhibited ridaifen-B-induced apoptosis. These results suggest that the induction of apoptosis by ridaifen-B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement.
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PMID:Induction of mitochondria-involved apoptosis in estrogen receptor-negative cells by a novel tamoxifen derivative, ridaifen-B. 1816 32


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