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)

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
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PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

The Bcl-2 proto-oncogene product blocks apoptosis. We retrospectively studied Bcl-2 expression in 124 primary tumors from patients diagnosed with T1 (2 cm or less) breast carcinoma with (T1N1) or without (T1N0) lymph-node metastasis. Bcl-2 protein was detected by immunohistochemistry on paraffin-embedded tissue sections. Multivariate logistic regression modeling was used to estimate prevalence odds ratios for lymph-node metastasis. Bcl-2 was widely expressed among T1 tumors showing a strong positive relationship with estrogen (ER)- and progesterone (PR)-receptor-positive tumors. However, a significant inverse correlation was seen between Bcl-2 expression and histological grade, Bcl-2 being absent in the majority of T1 undifferentiated tumors (grade-III carcinomas). Furthermore, Bcl-2 was more frequently expressed in T1N1 cases (72.2%) than in T1N0 specimens (45.7%). The odds for lymph-node metastasis in the Bcl-2-positive group was 3.6 times larger than that in the Bcl-2-negative group. The co-expression of PR significantly modified the effect of Bcl-2 on the odds for lymph-node metastasis, suggesting the existence of a synergistic interaction between the 2 parameters. We studied the percentage of dead cells in primary tumors by in situ DNA fragmentation (FDNA), and found an inverse correlation between Bcl-2 expression and FDNA. This supported the hypothesis that Bcl-2 extends cell survival. In conclusion, our study provides evidence that Bcl-2 expression is involved in breast-cancer progression, at least in a subset of well-differentiated and PR-positive tumors.
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PMID:Bcl-2 expression is associated with lymph node metastasis in human ductal breast carcinoma. 781 52

We report overexpression of the proto-oncogene bcl-2 in gastrointestinal adenocarcinoma and its precursor lesions. The bcl-2 proto-oncogene is centrally involved in the oncogenesis of human follicular lymphoma via a chromosomal translocation t(14;18)(q32;q21) and is also expressed in the epithelial regenerative compartment or the basal crypts of the normal colon and small intestine. We describe an immunohistochemical analysis of fixed, paraffin-embedded tissue using both a polyclonal rabbit and a monoclonal mouse antibody to the Bcl-2 protein. In addition to confirming bcl-2 expression in normal colonic and small intestinal crypts, we also observed expression in the gastric epithelial regenerative compartment, the mucous neck region. No increased expression was found in nonneoplastic or inflammatory gastrointestinal conditions, including ulcerative colitis, Crohn's disease, or inflammatory or hamartomatous polyps. Increased bcl-2 expression, however, was present in hyperplastic colonic polyps and in the majority of dysplastic lesions, from the earliest precursors through large adenomas, high grade flat dysplasia, and adenocarcinoma, all in comparison with adjacent internal control normal epithelium. Increased expression was present in dysplastic glandular lesions from all gastrointestinal sites, including colon, small bowel, and stomach. Furthermore, bcl-2 expression was frequently abnormal in nondysplastic epithelium surrounding dysplastic lesions, suggesting that altered expression occurred before the development of morphological dysplasia. Specifically, directly contiguous morphologically nondysplastic epithelium often showed abnormal bcl-2 expression throughout the full length of the crypt-villus axis. This expression pattern gradually diminished to involve only the crypt base (the normal pattern of expression), proceeding away from malignant or dysplastic lesions. Abnormal bcl-2 immunoreactivity in 1), the earliest precursor dysplastic lesions and its persistence throughout neoplastic progression and 2), contiguous morphologically unaltered nondysplastic epithelium suggests that bcl-2 alterations occur early during the morphological and molecular sequence of events leading to gastrointestinal epithelial neoplasia.
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PMID:The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model. 785 28

Expression of several members of the BCL-2 family of genes was investigated by immunohistochemical methods in 30 primary colorectal adenocarcinomas and 24 adenomatous polyps. When compared to the intensity observed in adjacent normal mucosal epithelial cells, the intensity of Bcl-X immunostaining was elevated in 18 of 30 (60%) carcinomas (P = 0.0001) and 12 of 24 (50%) adenomatous polyps (P = 0.0001). Immunoblot analysis of five pairs of tumors and adjacent normal colonic tissue indicated marked elevations in the relative levels of the anti-apoptotic Bcl-XL, protein in all cases. In contrast to the increased Bcl-X expression, the intensity of Bcl-2 immunostaining was greater than that of normal colonic mucosa in only 3 of 30 (10%) carcinomas and, in fact, was lower than that of adjacent normal epithelia] cells in 25 (83%) cases (P = 0.0001). Furthermore, the percentage of Bcl-2 immunopositive cells was generally lower in carcinomas than in adenomas (mean +/- SE, 44 +/- 6% versus 73 +/- 5%, respectively; P = 0.001) and in moderately or poorly differentiated tumors than in well-differentiated tumors (39 +/- 6% versus 70 +/- 11%, respectively; P = 0.045). In addition, the proportion of tumors in which the Bcl-2 immunointensity was more than or equal to that of normal colonic mucosa was significantly lower in carcinomas than adenomas (5 of 30 versus 15 of 24, respectively; P < 0.001), suggesting that decreases in Bcl-2 expression represent a later event associated with the progression of colorectal cancers. When compared to that of normal adjacent colonic epithelium, the intensity of Mcl-1 immunostaining was reduced in 20 of 30 (67%) of carcinomas (P = 0.0001) compared to only 1 of 24 adenomas, suggesting that decreases in Mcl-1 expression represent a later event associated with progression from a benign to a malignant phenotype or with transition to a less-differentiated state, because most of the carcinomas evaluated here (25 of 30; 83%) were not well differentiated. The intensity of immunostaining for the pro-apoptotic protein Bak was reduced compared to that of normal mucosal epithelial cells in 27 of 30 (90%) carcinomas and 22 of 24 (92%) adenomas, suggesting that reductions in Bak expression occur early in colorectal tumor progression (P = 0.0001). In contrast, the intensity of immunostaining for the pro-apoptotic protein Bax was not significantly altered in carcinomas; compared to that of normal colonic mucosa, Bax immunointensity was reduced in only 7 of 30 (23%) carcinomas and 3 of 24 (13%) adenomas, and the percentage of Bax immunopositive cells was also not significantly different in any of the histological subgroups. Taken together, these results suggest that expression of Bcl-XL is increased in undifferentiated primary colorectal cancers, often with accompanying reciprocal decreases in the anti-apoptotic proteins Bcl-2 and Mcl-1 and the pro-apoptotic protein Bak, whereas Bax expression is relatively constant. Thus, a shift from expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 to the Bcl-XL protein may occur during progression of colorectal tumors.
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PMID:Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. 862 22

Control of transformed cells by neighbouring normal cells is known since the beginning of transformation studies in vitro. The classical explanation for this phenomenon is based on proliferation inhibition of transformed cells by normal cells. We extend this model by presenting data that show that TGF-beta-treated normal cells can eliminate transformed cells by induction of apoptosis. Both the TGF-beta-induced signal pathway in normal cells, leading to the production of a short-lived apoptosis-inducing factor, as well as the specific interaction of this factor with transformed cells depend on the action of reactive oxygen species. Sensitivity to induction of apoptosis seems to be a common feature associated with the transformed state, independent of the originally transforming principle. Therefore, tumor development should require either interference with the process of elimination or acquisition of resistance against it. We discuss experimental evidence for interfering substances, such as antioxidants, as well as for genetic systems that protect transformed cells from the negative effects of their cellular environment, such as Bcl-2 or papilloma viruses. These findings, as well as the general resistance of exvivo tumor cells against induction of apoptosis are in line with the novel model of control of tumor progression presented by us in this review.
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PMID:Elimination of transformed cells by normal cells: a novel concept for the control of carcinogenesis. 872 Apr 67

The current paradigm states that cancer progression is caused by random independent mutations, each selected for its survival advantages. The accelerated rates of phenotypic changes, the pleiotropic effect of several genes involved in progression--which need not be necessarily mutated for inducing the observed changes in cancer cell behaviour--lead us to propose an alternative hypothesis. Malignant progression might be a result of the unveiling of a cell-survival program, induced by various aggressions in the same way as the SOS system is induced and regulated in bacteria. This hypothesis depends on the homology between several genes involved in cancer progression (such as bcl2, mdm2, the mismatch repair genes, the heat shock protein genes, the pleiotropic resistance genes, the telomerase gene ...) and several genes involved in the survival of prokaryotes and eukaryotes under stress. The development of multicellular organisms could not take place without the building of a control program, exemplified by the so-called anti-oncogenes. However, this control program had to integrate some weaknesses, in order to allow for embryogenesis, growth, and wound healing. These weaknesses, neutral from an evolutionary point of view--since most cancers are sporadic and kill their hosts long after the birth of the offspring--are exploited by the survival program of individual cells, inherited from the genome of prokaryotes and unicellular eukaryotes, and repressed but not suppressed in animals. If this theory is true, it is probable that (i) no anti-oncogenes will be found in unicellular organisms, (ii) the sensitivity to mutations will be higher in genes involved in proliferation and in anti-oncogenes such as p53 and Rb, than in genes not involved in the cancer process, (iii) a process of transfer of genetic information exists in cancer cells as it exists in bacteria. The identification of the genes governing the survival program could lead to new therapeutic approaches.
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PMID:Tumour progression: random mutations or an integrated survival response to cellular stress conserved from unicellular organisms? 873 76

Apoptosis or programmed cell death represents a mechanism by which tumor cells with DNA damage can be deleted. Bcl-2 and p53 gene products have both been linked to apoptosis. Bcl-2 plays a role as an inhibitor of apoptosis that may extend the viability of cells containing genetic alterations and facilitate tumor progression. Mutant p53 has a similar effect. The purpose of this study was to investigate the relationship between bcl-2 and p53 expression and to clarify their roles in apoptosis in different histological graded breast carcinomas. We analysed 101 invasive ductal carcinomas of the breast for the expression of bcl-2, p53, c-erbB-2, estrogen and progesterone receptors using immunohistochemistry. Reciprocal expression of bcl-2 and p53 was present in 71.3% of cases. The bcl-2+/p53-expression pattern was prevalent in histological grade I and II tumors (77.4% and 59.3% respectively) and rarely present in histological grade III (6.3%). Conversely, bcl-2-/p53+ expression pattern was rarely present in histological grade I and II tumors (3.2% and 11.1% respectively) and prevalent in histological grade III (50.0%). Our results also showed that Bcl-2 expression was positively correlated with ER and PR, more prevalent in pre-menopausal status, and negatively correlated with cerbB-2 expression. Bcl-2 expression was involved in tumor progression in well-differentiated tumors and mutant p53 could substitute for bcl-2 function in poorly differentiated tumors. The bcl-2/p53 expression pattern of tumors may be of value in predicting therapeutic response and prognosis. Bcl-2 expression was correlated with other well-established prognostic factors and bcl-2 could be an estrogen-related protein.
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PMID:Reciprocal expression of Bcl-2 and p53 in breast ductal carcinoma. 891 21

The expression of Bcl-2, Bcl-X, Mcl-1, and Bax was examined by immunohistochemical methods in 93 tumors of nervous system origin, including 49 gliomas (30 astrocytomas and 19 glioblastoma multiforme (GMs)), 16 medulloblastomas (MBs), 19 neuroblastomas (NBs; 9 undifferentiated and 10 differentiated), and 9 miscellaneous neuroectodermal neoplasms. Among the 49 gliomas, immunopositivity (defined as > or = 10%) was observed for Bcl-2 in 45 (92%), Bcl-X in 48 (98%), Mcl-1 in 49 (100%), and Bax in 48 (98%) of 49 specimens. In 11 (37%) of 30 astrocytomas (WHO grades I to III), the tumor specimens were composed predominantly of malignant cells with strong-intensity Bcl-2 immunostaining, whereas none of the 19 GMs (WHO grade IV) exhibited strong-intensity Bcl-2 immunoreactivity (P = 0.001). Similarly, Mcl-1 immunointensity was strong in 15 (50%) of 30 astrocytomas, compared with only 2 (11%) of 19 GMs (P = 0.005). The percentage of Mcl-1-immunopositive tumor cells was also higher in astrocytomas than GMs (P < 0.002). Thus, contrary to a priori expectations, the expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 was significantly higher in astrocytomas than in GMs. Of the 16 MBs, immunopositivity was found for Bcl-2 in 4 (25%), Bcl-X in 9 (56%), Mcl-1 in 8 (50%), and Bax in 16 (100%) of the cases. The intensity of immunostaining was strong for Bcl-2 in only 1 (6%) specimen, for Bcl-X in 3 (19%), and for Mcl-1 in 2 (12.5%), in contrast to Bax immunostaining, which was strong in 12 (75%) tumors. Significantly higher percentages of Bax-immunopositive tumor cells were also found in MBs, compared with Bcl-2, Bcl-X, and Mcl-1 (P < 0.0001). All 19 NBs were immunopositive for Bcl-2, Bcl-X, Mcl-1, and Bax. Higher percentages of Bcl-X- and Mcl-1-immunopositive tumor cells were observed in well differentiated tumors (P = 0.04 and 0.004, respectively). The intensity of Mcl-1 immunostaining was also generally higher in differentiated than undifferentiated NBs (strong immunointensity in 7 of 10 versus 0 of 9; P = 0.002). Conversely, strong-intensity Bax immunostaining was associated with undifferentiated histology (5 of 9 (56%) versus 1 of 10 (10%); P = 0.03). Taken together, these findings begin to delineate trends in the regulation of the relative levels of the Bcl-2 family proteins, Bcl-2, Bcl-X, Mcl-1, and Bax in gliomas, MBs, NBs, and some of their histological subtypes. The suggestion that expression of some of these Bcl-2 family genes may be differentially regulated in association with tumor progression and differentiation provides insights into the diverse biology and clinical behavior of these tumors of nervous system origin.
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PMID:Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. 906 Aug 18

Recent study has demonstrated the development of pregnancy-dependent mammary tumors (PDMTs) in GR/A mice during pregnancy and their regression by apoptotic cell death after parturition. In the present study, we examined the molecular machinery of PDMTs before and after parturition and in progression. The death associated-cell surface molecule Fas was expressed only when apoptosis occurred, and no expression could be determined after progression. Interestingly, death suppressor Bcl-2 showed down-regulation when apoptosis occurred, and intense expression after progression. Examination of the possible involvement of PKC isozymes showed that only PKC-epsilon showed drastic changes in expression: expression was not detected in normal mammary gland cells and PDMTs, but was instead seen only when PDMTs progressed to malignant tumors. On the basis of these results, we suggest that PDMT-regression is due to Fas-mediated apoptosis, and that lack of Fas, persistent expression of Bcl-2, and new expression of PKC-epsilon are essential events for tumor progression.
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PMID:Progression of PDMT is accompanied by lack of Fas and intense expression of Bcl-2 and PKC-epsilon. 916 71

Induction of apoptosis in transformed fibroblasts by surrounding normal cells has been discussed as a potent early control step in carcinogenesis. According to this hypothesis, tumor progression should require resistance of transformed cells against this TGF-beta-triggered control mechanism. Here we show that Bcl-2, a protein involved in inhibition of apoptosis, can protect transformed cells from induction of apoptosis by surrounding cells. Rather than acting on the transformation process itself, Bcl-2 may thus represent an efficient modulator of carcinogenesis at an intercellular level.
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PMID:Interference of bcl-2 with intercellular control of carcinogenesis. 917 29


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