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)

Programmed cell death, or apoptosis, is inhibited by the antiapoptotic oncogene, Bcl-2, and is mediated by a cascade of aspartate-specific cysteine proteases, or caspases, related to interleukin 1-beta converting enzyme. Depending on cell type, apoptosis can be induced by treatment with thapsigargin (TG); a selective inhibitor of the endoplasmic reticulum-associated calcium-ATPase. The role of caspases in mediating TG-induced apoptosis was investigated in the Bcl-2-negative human breast cancer cell line, MDA-MB-468. Apoptosis developed in MDA-MB-468 cells over a period of 24-72 h following treatment with 100 nM TG, and was prevented by Bcl-2 overexpression. TG-induced apoptosis was associated with activation of caspase-3 and was inhibited by stable expression of the baculovirus p35 protein, an inhibitor of caspase activity. Also, TG-induced apoptosis was inhibited by treating cells with Z-VAD-fmk, a cell-permeable fluoromethylketone inhibitor of caspases. These findings indicate that TG-induced apoptosis of MDA-MB-468 breast cancer cells is subject to inhibition by Bcl-2 and is mediated by caspase activity. This model system should be useful for further investigation directed toward understanding the role of calcium in signaling apoptosis, and its relationship to Bcl-2 and the caspase proteolytic cascade.
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PMID:Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells. 929 14

Human chorionic gonadotropin (hCG) inhibits the progression of 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinomas. In order to determine whether this phenomenon was mediated by induction of programmed cell death or apoptosis, 45-day-old virgin Sprague-Dawley rats received 8 mg DMBA/100 g body weight; 20 days later they were injected daily with 100 IU hCG for 40 days (DMBA + hCG group). Age-matched untreated, hCG- and DMBA + saline treated rats were used as controls. Tissues were collected at the time of DMBA administration and at 5, 10, 20 and 40 days of hCG injection. RNA from mammary glands, adenocarcinomas and ovaries was probed for transforming growth factors (TGF) alpha and beta, and the apoptotic genes TRPM2, ICE, bcl2, bcl-XL, bcl-XS, p53 and c-myc. The mammary glands of hCG-treated animals with or without DMBA exhibited elevated expression of TRPM2, ICE, bcl-XS, c-myc and p53; and elevation in the apoptotic index. Mammary adenocarcinomas developed in those animals treated with hCG showed an elevation in the expression of p53, c-myc and ICE genes in comparison with the levels detected in the adenocarcinomas developed by the animals treated with DMBA alone. No significant alterations in the expression of any of the genes tested was observed in ovarian RNAs. These results led us to conclude that hCG induces programmed cell death in the mammary gland initiated in the carcinogenic process, that this process is p53 dependent, and is modulated by c-myc expression. Our data also indicate the possibility that a cell death program dependent on the bcl2 family exists, because of the potential involvement of p53, bcl-XS and Bax in apoptosis. This additional mechanism of tumor inhibition makes hCG treatment a useful approach for the prevention and therapy of breast cancer.
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PMID:Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death. 932 78

Bcl-2 protein has been shown to contribute to oncogenesis because it can transform and immortalize cells in cooperation with c-myc, ras, or viral genes. However, in vivo studies have not yet established whether bcl-2 can play a role in metastasis. Here we investigate the potential metastatic role of bcl-2. We introduced the human bcl-2 gene into a low bcl-2 expressing human breast cancer cell line MCF7 ADR. We demonstrate that two bcl-2 overexpressing clones injected intravenously or intramuscularly into nude mice induce a significantly higher number of experimental and spontaneous lung metastases compared to the control transfectant clone. We demonstrate that bcl-2 overexpressing clones are more invasive and migratory in response to chemotactic stimuli than the control transfectant clone. Furthermore, zymographic analysis shows that secretion of 72 and 92 kDa gelatinases increases in the two bcl-2 overexpressing transfectants. Tumors originating from bcl-2 overexpressing clones also show a decrease in the latency period of tumor appearance. In conclusion, our data show that bcl-2 overexpression enhances both tumorigenicity and metastatic potential of MCF7 ADR cells by inducing metastasis-associated properties.
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PMID:Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. 933 47

Basic fibroblast growth factor (bFGF) is a mitogen and a survival factor in fibroblasts and endothelial cells. It acts as an angiogenesis factor in breast cancer, but paradoxically inhibits proliferation in several breast cancer cell lines. In this study, we investigated the effects of bFGF on the survival of MCF-7 human breast cancer cells in order to determine if these effects were also opposite to those in fibroblasts. Incubation of NIH 3T3 cells with bFGF for 24 h caused an approximately 30% increase in day 12 +/- 2 adherent colonies while causing an approximately 50% decrease in MCF-7 colony formation. Incubation of NIH 3T3 cells with bFGF prior to etoposide or 5-fluorouracil treatment caused a proportionally smaller decrease in colony forming efficiency as a result of drug treatment, while preincubation of MCF-7 cells with bFGF caused a similar but opposite additive increase in drug-induced diminution of colony forming efficiency. These effects on MCF-7 cells were observed at variable times of incubation and doses of etoposide to 1 microM and 5-fluorouracil to 200 microM and at variable times of incubation and concentrations of bFGF to 1 ng/ml. Incubating with bFGF after drug exposure had similar effects on the reduction of cloning efficiency. The effects of bFGF were similar on programmed cell death, as determined by morphologic characteristics of apoptosis on 400 cell counts and FITC-dUTP 3'-OH DNA end labeling. Basic FGF promoted apoptosis and increased the rate of drug-induced cell death with both etoposide and 5-fluorouracil. While recombinant bFGF affected Bcl-2 protein and mRNA levels in NIH 3T3 cells only marginally and variably and had no discernible effects on Bax protein levels, it markedly downregulated Bcl-2 mRNA and protein levels in MCF-7 cells and caused an increase in Bax protein levels. These changes resulted in a decreased association of Bcl-2 with immunoprecipitable Bax and an increased association of Bax with immunoprecipitable Bcl-2 in MCF-7 cells treated with bFGF. These data suggest that bFGF may cause different phenotypic responses in breast cancer cells from those in surrounding cells and offer one possible mechanism through opposite regulation of Bcl-2 and Bax. Inhibition of colony formation by bFGF was observed in several breast cancer cells lines, demonstrating that this effect demonstrated in MCF-7 cells was more universal.
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PMID:Basic fibroblast growth factor downregulates Bcl-2 and promotes apoptosis in MCF-7 human breast cancer cells. 945 70

Cystatin A (acid cysteine proteinase inhibitor; ACPI) is a natural inhibitor of cysteine proteinases. It has been suggested that an inverse correlation exists between cystatin A and malignant progression. We wanted to assess the biological and clinical significance of cystatin A in infiltrative breast carcinoma by immunohistochemical staining. Formalin-fixed paraffin-embedded material from 440 cases treated during the years 1988-1991 was used in the study. After exclusion of patients with disseminated disease at diagnosis, previous contralateral breast carcinoma, and absence of follow-up data, 384 patients could be included in the survival analysis. For immunohistochemical analysis of cystatin A, we used monoclonal cystatin A antibody WR-23/2/3/3, the binding of which was detected by the avidin-biotin-peroxidase method. Immunohistochemical analysis of Bcl-2 and p53 was also done, and mitotic activity was evaluated. Positive staining for cystatin A was found in 52 of 440 cases. The staining was irregular but showed irrefutably positive areas within neoplastic tissue. Most of the positive tumors were of the ductal infiltrative type, but two were mucinous carcinomas, one medullary and one squamous cell carcinoma. No lobular carcinomas showed positive staining. Focal cystatin A positivity was seen in myoepithelial cells of benign ducts. Occasional apoptotic bodies within the neoplasm showed strong positivity for cystatin A. Tumors positive for cystatin A were of larger size and had higher mitotic activity than cystatin A-negative tumors. Cystatin A was associated with negative Bcl-2 staining, but there was no statistically significant association between axillary lymph node status or p53 immunostaining. The risk for breast cancer-related death was significantly higher in patients with cystatin A-positive tumors than in those with cystatin A-negative ones. The risk increase was significant also in lymph node-negative patients. After adjusting for the effect of tumor size, histological grade, and lymph node status, cystatin A-positive patients still had a higher risk of death. Patients with cystatin A and p53 coexpression had a higher risk of death than the other patients. The findings reveal a new variant of aggressive breast cancer. This type of carcinoma may develop during tumor progression through genetic instability that allows cystatin A expression and gives growth advantage to a clone of tumor cells.
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PMID:Cysteine proteinase inhibitor cystatin A in breast cancer. 945 85

The expression of several apoptosis-regulating genes was evaluated in 9 human breast cancer cell lines, 2 immortalized human mammary epithelial lines, 1 normal breast tissue biopsy, and 3 primary breast tumors, using a multiple antigen detection (MAD) immunoblotting method. The anti-apoptotic proteins Bcl-2, Bcl-X(L), Mcl-1, and BAG-1 were present at immunodetectable levels in 7, 10, 10, and 9 of the 11 lines. Comparing these 11 cell lines among themselves revealed that steady-state levels of Bcl-2, Bcl-X(L), Mcl-1, and BAG-1 were present at relatively higher levels in 4, 6, 5, and 5 of the lines, respectively. In contrast, the pro-apoptotic proteins Bax and Bak were detected in all 11 cell lines, and were present at relatively higher levels in 10 and 5 of the 11 lines, respectively. The Interleukin-1beta converting enzyme (ICE) homolog CPP32 (Caspase-3) was expressed in 10/11 breast cell lines. High levels of p53 protein, indicative of mutant p53, were found in 8 of the 11 lines and correlated inversely with Bax expression (p = 0.01). Bcl-2 and BAG-1 protein levels were positively correlated (p = 0.03). Immunoblot analysis of primary adenocarcinomas revealed expression of the anti-apoptotic proteins Bcl-2, Bcl-X(L), Mcl-1, and BAG-1, as well as the pro-apoptotic proteins Bax, Bak, and CPP32, in at least 2 of the 3 tumors examined. Immunohistochemical analysis was also performed for all of these proteins using 20 paraffin-embedded breast cancer biopsy specimens that all contained residual normal mammary epithelium in combination with both invasive cancer and carcinoma in situ. All of these apoptosis-regulating proteins were detected in primary breast cancers, though the percentage of immunopositive tumor cells varied widely in some cases. Comparisons of the intensity of immunostaining in normal mammary epithelium and invasive carcinoma suggested that Bcl-2 immunointensity tends to be lower in cancers than normal breast epithelium (p = 0.03), whereas CPP32 immunointensity was generally higher in invasive cancers (p < 0.0001). Taken together, the results demonstrate expression of multiple apoptosis-modulating proteins in breast cancer cell lines and primary tumors, suggesting complexity in the regulation of apoptosis in these neoplasms of mammary epithelial origin.
Breast Cancer Res Treat 1998 Jan
PMID:Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors. 949 1

Bcl-2 has been demonstrated to inhibit apoptosis in breast cancer cells in vitro, and the ratio between Bcl-2 and its proapoptotic homologue Bax seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl-2 and the rate of apoptotic and necrotic cell death in breast tumours. From a series of 441 premenopausal, lymphnode-negative breast cancer patients, a subset of 49 tumours was selected in which immunostaining for the 26-kDa isoform of Bcl-2 was either absent (n = 23) or very high (n = 26). High expression of Bcl-2 was found to be strongly associated with low rates of apoptotic (P < 0.001) and necrotic cell death (P < 0.001). The mean value of the apoptotic index was 2.69%+/-1.40% in Bcl-2-negative tumours and 0.68%+/-1.00% in Bcl-2-positive tumours. Expression of the proapoptotic protein Bax correlated neither with Bcl-2 nor with the frequency of apoptotic cells. Immunostaining for the antiapoptotic Bcl-2 homologue BcI-X(L) correlated with Bcl-2 expression (P < 0.001) but not with apoptosis. High proliferation rate and high tumour grade (Bloom-Richardson) were strongly associated with absence of Bcl-2 expression (P< 0.001). p53 accumulation was associated with absence of Bcl-2 expression and increased apoptotic activity. Loss of Bcl-2 expression was strongly correlated with increased apoptotic and necrotic cell death, high proliferation rate and high tumour grade, supporting a model in which Bcl-2 not only mediates cell death, but also cell division in breast cancer tissue, and in which regulation of cell division and cell death are tightly linked.
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PMID:Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity. 951 59

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and its synthetic analog EB1089 induce characteristic morphological features of apoptosis in MCF-7 cells in vitro that coincide with up-regulation of clusterin and cathepsin B, proteins associated with apoptosis in the mammary gland, and with down-regulation of Bcl-2, an antiapoptotic protein. To determine whether vitamin D3 compounds could mediate apoptosis of breast tumors in vivo, we treated nude mice carrying established MCF-7 xenografts with the low calcemic vitamin D3 analog EB1089 via daily injection or sustained release pellets for up to 5 weeks. The volume of tumors from mice treated with 45 pmol/day EB1089 was 4-fold lower than that of tumors from vehicle-treated control mice after 5 weeks. The reduced growth of tumors from EB1089-treated mice was associated with characteristic apoptotic morphology and a marked reduction in the proportion of epithelial cells to stroma. After 5 weeks of treatment with EB1089, MCF-7 tumors exhibited a 6-fold increase in DNA fragmentation (as measured by in situ end labeling) relative to that in control tumors. The enhanced rate of apoptosis in tumors from EB1089-treated mice was coupled to a 2-fold reduction in proliferation (as measured by expression of proliferating cell nuclear antigen) compared with that in tumors from control mice. The antitumor effects of EB1089 were evident at doses that had minimal effects on serum calcium and body weight. EB1089 treatment did not alter the growth of xenografts derived from a vitamin D3-resistant variant of MCF-7 cells (MCF-7(D3Res) cells), which display resistance to EB1089 in vitro, indicating that resistance to EB1089 is maintained in vivo. Tumors derived from both MCF-7 and MCF-7(D3Res) cells underwent apoptotic regression upon estradiol withdrawal, indicating comparable estrogen dependence of tumors with differential sensitivity to vitamin D3 compounds. These are the first studies to demonstrate apoptotic morphology and regression of human breast tumors in response to treatment with a vitamin D3 analog in vivo and support the concept that vitamin D3 compounds can effectively target human breast cancer.
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PMID:Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089. 952 99

Experimental laboratory data suggest that tumour growth is a balance between apoptosis and proliferation and that suppression of drug-induced apoptosis by oncogenes such as bcl-2 may be an important cause of intrinsic chemoresistance. The aims of this study were to assess the in vivo relationship of apoptosis to proliferation and Bcl-2 protein in human breast tumours both prior to chemotherapy and in the residual resistant cell population at the completion of treatment. We examined apoptotic index (AI), Ki67 and Bcl-2 protein expression in the tissue of 40 patients with operable breast cancer immediately before ECF preoperative chemotherapy, and in 20 of these patients with residual tumour, at the completion of treatment. There was a significant positive association between AI and Ki67 both before and after chemotherapy, and in their percentage change with treatment. In the residual specimens AI and Ki67 were significantly reduced compared with pre-treatment biopsies, while Bcl-2 expression showed a significant increase. No differences were seen in the pre-treatment levels of any of the variables measured between patients obtaining pathological complete response and those who did not, although numbers were small. These data suggest that apoptosis and proliferation are closely related in vivo. It is possible that the phenotype of reduced apoptosis and proliferation, and increased Bcl-2 may be associated with breast cancer cells resistant to cytotoxic chemotherapy, although this can only be proven by assessing larger numbers of patients in relation to pathological response.
Breast Cancer Res Treat 1998 Mar
PMID:Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. 959 82

BAG-1 (also known as RAP46) is an anti-apoptotic protein, which has been shown previously to interact with a number of nuclear hormone receptors, including receptors for glucocorticoid, estrogen, and thyroid hormone. We show here that BAG-1 also interacts with retinoic acid receptor (RAR). Gel retardation assays demonstrated that in vitro translated BAG-1 protein could effectively inhibit the binding of RAR but not retinoid X receptor (RXR) to a number of retinoic acid (RA) response elements (RAREs). A glutathione S-transferase-BAG-1 fusion protein also specifically bound RAR but not RXR. Interaction of BAG-1 and RAR could also be demonstrated by yeast two-hybrid assays. In transient transfection assays, co-transfection of BAG-1 expression plasmid inhibited the transactivation activity of RAR/RXR heterodimers but not RXR/RXR homodimers. When stably expressed in breast cancer cell lines, BAG-1 inhibited binding of RAR/RXR heterodimer to a number of RAREs and suppressed RA-induced growth inhibition and apoptosis. In addition, RA-induced suppression of Bcl-2 expression was abrogated by overexpression of BAG-1. These results demonstrate that BAG-1 can regulate retinoid activities through its interaction with RAR and suggest that elevated levels of BAG-1 protein could potentially contribute to retinoid resistance in cancer cells.
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PMID:Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells. 964 62


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