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)

Angiomyofibroblastoma (AMF) is a rare, benign, mesenchymal tumor occurring mainly in the female genital tract. Some cases contain scattered mature adipocytes, but the lipomatous variant in which mature adipose tissue is prominent or striking is rare. Only five cases have been reported in the English literature. We report two more such cases that were composed of 70 to 80% and 30 to 40% adipose tissue, respectively. Immunohistochemical analysis showed that the tumor cells were positive for estrogen receptor, progesterone receptor, vimentin, and Bcl-2, and negative for cytokeratin AE1/1, EMA, and CD117. Tumor cells in the first case were positive for CD34 but not desmin and muscle-specific actin. The opposite expression profile of these three markers was observed in tumor cells in the second case: positive for desmin and muscle-specific actin and negative for CD34. Rare cells were positive for S-100 in adipose-rich areas in the first case. Our findings indicate that the tumor cells in the lipomatous variant have similar immunoprofile to those of usual AMF and support the concept that the lipomatous variant probably represents an extreme end of a wide spectrum of differentiation in AMF.
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PMID:Lipomatous variant of angiomyofibroblastoma: report of two cases and review of the literature. 1578 77

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

We have investigated the effect of estrogen on p53 cellular location and its influence on tumor cell susceptibility to tumor necrosis factor (TNF)-mediated cytotoxic action. For this purpose, we have used the TNF-sensitive human breast adenocarcinoma MCF-7 and its derivative, the TNF-resistant 1001 clone. Our data indicate that although estrogen receptor (ER)alpha is present in both cell lines, estrogen treatment (1x10(-8) M) has an influence only on the MCF-7 cells and protects these cells from the TNF cytotoxicity. This protective effect is associated with translocation of p53 from the nucleus to the cytoplasm in p53 wild-type MCF-7 and not in p53-mutated 1001 cells. The translocation of p53 in MCF-7 cells results in a decrease in its transcriptional activity, as revealed by diminished p21(WAF1/CIP1) induction and an altered ratio of Bax and Bcl-2 proteins. The estrogen-induced effects are reversed by the selective estrogen inhibitor 182, 780 (1x10(-6) M). Interestingly, transient transfection of MCF-7 cells with ERbeta but not ERalpha cDNA encoding plasmid results in retention of p53 in the nucleus, a subsequent potentiation of its transcriptional activity, and in an increased MCF-7 sensitivity to TNF. The estrogen effects on p53 location and transcriptional activity may involve the mdm2 protein since both events were reversed following MCF-7 transfection with plasmid encoding the ARF cDNA. These studies suggest that estrogen-induced MCF-7 cell survival in the presence of TNF requires a transcriptionally active p53 and, more importantly, indicate that introduction of ERbeta can attenuate the estrogen effects on the p53 protein location, its transcriptional activity and also results in a potentiation of cell sensitivity to TNF-mediated cell death.
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PMID:Opposite effects of estrogen receptors alpha and beta on MCF-7 sensitivity to the cytotoxic action of TNF and p53 activity. 1587 Jul 4

Postmenopausal women with estrogen receptor positive (ER(+)) breast cancer frequently respond paradoxically to estrogen administration with tumor regression. Using both LTED and E8CASS cells derived from MCF-7 breast cancer cells by long-term estrogen-deprivation, we previously reported that 17beta -estradiol (estradiol) is a powerful, pro-apoptotic hormone which kills the cancer cells through activation of the Fas/FasL death receptor pathway. We postulated that the mitochondrial interactive protein Bcl-2 might play a role in the regulation of estradiol-induced apoptosis in both LTED and E8CASS cells. In this study, we assessed estradiol effects on cell growth, proliferation and apoptosis. Additionally we investigated the effect of estradiol on caspase activation, NF-KB and Bcl-2 expression. The functional role of Bcl-2 in estradiol-induced apoptosis was further studied by knockdown or decrease of Bcl-2 with siRNA. Our results show that estradiol significantly inhibited cell growth primarily through a pro-apoptotic action involving caspase-7 and 9 activations (p < 0.01). Basal Bcl-2 and NF-KB levels were greatly elevated and estradiol decreased NF-KB, but not Bcl-2 expression. Knockdown of Bcl-2 expression with siRNA decreased the levels of this protein by 9 fold (p < 0.01). This reduction markedly sensitized both LTED and E8CASS cells to the pro-apoptotic action of estradiol, leading to a synergistic induction of apoptosis and a concomitant reduction in cell number (p < 0.01). Therefore, down-regulation of Bcl-2 synergistically enhanced estradiol-induced apoptosis in ER(+) postmenopausal breast cancer cells.
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PMID:Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER(+) breast cancer cells. 1590 28

Recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain. Clinical reports have documented the effectiveness of estrogens to attenuate symptoms associated with Parkinson's disease, and to reduce the risk of Alzheimer's disease and cerebrovascular stroke. This evidence is corroborated by numerous experimental studies documenting the protective role of female sex hormones both in vitro and in vivo. Accordingly, estrogens have been shown to promote survival and differentiation of several neuronal populations maintained in culture, and to reduce cell death associated with excitotoxicity, oxidative stress, serum deprivation or exposure to beta-amyloid. The neuroprotective effects of estrogens have been widely documented in animal models of neurological disorders, such as Alzheimer's and Parkinson's diseases, as well as cerebral ischemia. Although estrogens are known to exert several direct effects on neurones, the cellular and molecular mechanisms implicated in their protective actions on the brain are not completely understood. Thus, on the basis of clinical and experimental evidence, in this review, we discuss recent findings concerning the neuronal effects of estrogens that may contribute to their neuroprotective actions. Both estrogen receptor-dependent and -independent mechanisms will be described. These include modulation of cell death regulators, such as Bcl-2, Akt and calpain, as well as interaction with growth factors, such as BDNF, NGF, IGF-I and their receptors. The anti-inflammatory effects of estrogens will also be described, namely their ability to reduce brain levels of inflammatory mediators, cytokines and chemokines. Finally, a brief overview about receptor-independent mechanisms of neuroprotection will aim at describing the antioxidant effects of estrogens, as well as their ability to modulate neurotransmission.
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PMID:From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. 1596 77

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

Polyamines and their rate-limiting enzyme, ornithine decarboxylase (ODC), are actively involved in cell growth and differentiation. The phytoestrogen genistein has been demonstrated to possess antitumor properties by influencing proliferation, differentiation, and apoptosis. The aim of this study was to investigate the effects of genistein at concentrations ranging from 0.01 to 100 microM on the polyamine biosynthesis, cell proliferation, and apoptosis in the estrogen receptor-positive DLD-1 human colon cancer cell line. Polyamine levels and ODC activity were evaluated by high performance liquid chromatography and radiometric technique, respectively. The proliferative response was estimated by [3H]-thymidine incorporation and the colorimetric 3-(4,5 di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Apoptosis was investigated by DNA fragmentation. Bax and Bcl-2 gene expressions were evaluated by multiplex-polymerase chain reaction. At concentration >or=1 microM, genistein decreased significantly the ODC activity and the polyamine levels. At the same concentration, genistein also increased significantly Bax mRNA expression, but not Bcl-2 mRNA expression. Higher concentrations (>or=10 microM) were needed to obtain a significant inhibition of cell proliferation and DNA fragmentation. The results of this study suggest that genistein can affect growth of DLD-1 cells by both decreasing polyamine biosynthesis and inducing apoptosis. However, further studies are required to assess the true ability of a soy rich diet in modifying colon cancer risk.
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PMID:Effects of genistein on the polyamine metabolism and cell growth in DLD-1 human colon cancer cells. 1609 Oct 8

Approximately 30-40% of estrogen receptor alpha (ERalpha)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERalpha-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERalpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERalpha-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE2) or prostaglandin F2alpha is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2alpha, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2 receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERalpha-positive breast cancer cells.
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PMID:Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells. 1612 22

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

In mammary pathology, adenosis tumor is defined as a clinically recognizable lesion that histologically primarily consists of adenosis, but also exhibits various combinations of diverse epithelial changes seen in other benign breast diseases. A lesion that occurred in the anogenital area of a 46-year-old woman and apparently arose in anogenital mammary-like glands is described and which, in our opinion, is best classified as adenosis tumor. A biopsy revealed a well-demarcated, unencapsulated lesion surrounded by compressed fibrous tissue forming a pseudocapsule. Several histological patterns within the same tumor mass were recognizable: sclerosing adenosis-like changes, variably sized microcysts and cysts, some with rare short papillary projections having hyalinized cores, rare tubular structures exhibiting epithelial features reminiscent of simple ductal hyperplasia, areas with oxyphilic (apocrine) metaplasia, and clear cell epithelial changes resembling mucinous metaplasia. Decapitation secretion was notable in many lumens. Rare lumens were filled with foamy macrophages. There were also focal clear cell changes of myoepithelial cells. The stroma was paucicellular and sclerotic in some foci and composed of myofibroblasts and myxoid in others. Calponin, actins, and p63 stained myoepithelial cells. The cells in the oxyphilic (apocrine) metaplasia areas stained for mitochondrial antigen and Bcl-2. Antibodies to progesterone and estrogen receptor stained approximately 50 and 20% of the epithelial cell population, respectively. Human androgen receptor gene analysis yielded a monoclonal pattern. As our case exhibited a number of patterns identical to those seen in diverse benign breast diseases, its classification as adenosis tumor seems justifiable. This cutaneous perianal lesion is indistinguishable microscopically from its mammary analogue and was clinically detectable.
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PMID:Adenosis tumor of anogenital mammary-like glands: a case report and demonstration of clonality by HUMARA assay. 1644 11


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